Benzimidazolone derivatives

ABSTRACT

This invention relates to benzimidazolone derivatives, represented by compounds of a general formula [I] 
                 
 
     [in which R 1  and R 2  stand for, e.g., hydrogen atoms; R 3a , R 3b , R 4 , R 5  stand for, e.g., hydrogen atoms and alkyl groups; R 6  stands for e.g., aryl or heteroaryl groups; A ring stands for 5- to 8-membered aliphatic heterocyclic ring containing one nitrogen atom; and Z stands for carbonyl group or sulfonyl group].  
     The benzimidazolone derivatives of the invention exhibit antagonism to muscarinic acetylcholine receptors, and are useful as treating agent and/or prophylactic of Parkinson&#39;s disease, drug-induced parkinsonism, dystonia, akinesia, pancreatitis, bilestone/cholecystitis, biliary dyskinesia, achalasia, pain, itch, cholinergic urticaria, irritable bowel syndrome, vomiting, nausea, dizziness, Meniere&#39;s disease, motion sickness and urinary disturbance.

TECHNICAL FIELD

[0001] This invention relates to substituted benzimidazolone derivativeswhich are useful in the field of pharmaceuticals. More specifically, theinvention relates to substituted benzimidazolone derivatives exhibitingselective antagonist activities against muscarinic acetylcholinereceptor M₁ and/or M₄ subtypes, which are useful as drug for thetreatment and/or prevention of Parkinson's disease, drug-inducedparkinsonism, dystonia, akinesia, pancreatitis, bilestone/cholecystitis,biliary dyskinesia, achalasia, pain, itch, cholinergic urticaria,irritable bowel syndrome, vomiting, nausea, dizziness, Meniere'sdisease, motion sickness such as space sickness, sea sickness and carsickness and urinary disturbance.

BACKGROUND ART

[0002] Muscarinic receptors have at least five subtypes (M₁ receptor, M₂receptor, M₃ receptor, M₄ receptor and M₅ receptor) which are present intissues or internal organs at different distribution levels.Non-selective muscarinic receptor antagonists represented by atropineand scopolamine, exhibit blocking actions of approximately the samelevel to these subtypes. These antagonists are effective for treating orpreventing dyskinesia such as Parkinson's disease, drug-inducedparkinsonism, dystonia and akinesia; diseases of digestive system suchas pancreatitis, bilestone/cholecystitis, biliary dyskinesia andachalasia; pain, itch, cholinergic urticaria, irritable bowel syndrome,vomiting, nausea, dizziness, Meniere's disease, motion sickness such asspace sickness, sea sickness and car sickness and urinary disturbance,but on the other hand induce such side effects as tachycardia, ocularhypertension, dry mouth, suppression of perspiration, mydriasis andconstipation, which frequently prevent their use in the doses sufficientto exhibit their efficacies [cf. Basic and Clinical Pharmacology, 4thed., (Appleton & Lange), pp.83-92 (1989); Drug News & Perspective,Vol.5, No.6, pp.345-352 (1992); The Merck Manual, 16th ed.,pp.1282-1283, P.1499 (1992)].

[0003] Recent research works indicate these side effects link to eitherone or both of M₂ receptor and M₃ receptor. That is, the side effectlike tachycardia is considered to be mainly attributable to M₂ receptorblockade, while dry mouth, suppression of perspiration, mydriasis andconstipation are considered to be caused mainly by M₃ receptor blockade[cf. Journal of Pharmacology & Experimental Therapeutics, Vol.292, No.3,pp.877-885 (2000); Proceedings of the National Academv of Sciences ofthe United States of America, Vol.97, No.17, pp.9579-9584 (2000)].

[0004] On the other hand, concerning dyskinesia such as Parkinson'sdisease, drug-induced parkinsonism, dystonia or akinesia, the involvemetof M₄ receptors is suggested. [cf. Proceedings of the National Academyof Sciences of the United States of America, Vol.96, No.18,pp.10483-10488 (1999)].

[0005] M₄ receptor is also suggested to take part in variousphysiological actions such as gallbladder contraction, relaxation ofbladder smooth muscles and pain [cf. Pharmacological Research, Vol.39,No.5, pp.389-395 (1999); Journal of Pharmacology & ExperimentalTherapeutics, Vol.283, No.2, pp.750-756 (1997); Journal of AutonomicPharmacology, Vol.18, No.4, pp.195-204 (1998); Journal of Pharmacology &Experimental Therapeutics, Vol.282, No. 1, pp.430-439 (1997)].

[0006] Furthermore, participation of M₁ receptor or M₄ receptor invomiting, nausea, dizziness, Meniere's disease and motion sickness issuggested by the data shown in the following papers [cf. NeurochemistryInternational, Vol.25, No.5, pp.455-464 (1994); Neuropharmacology,Vol.27, No.9, pp.949-956 (1988)].

[0007] Considering the foregoing, substances which exhibit selectiveantagonistic activities at M₁ or M₄ receptors and weak blocking effecton M₂ and M₃ receptors can be expected to have therapeutic effects onsuch diseases as Parkinson's disease, drug-induced parkinsonism,dystonia, akinesia, pancreatitis, bilestone/cholecystitis, biliarydyskinesia, achalasia, pain, itch, cholinergic urticaria, irritablebowel syndrome, vomiting, nausea, dizziness, Meniere's disease, motionsickness such as space sickness, sea sickness and car sickness andurinary disturbance, without inducing such side effects as tachycardia,dry mouth, suppression of perspiration, mydriasis or constipation.

[0008] Compounds resembling compounds of the present invention instructure are disclosed, e.g., in International Publications WO96/13262, WO 97/16192, WO 97/40035 and WO 99/32481, all of which share1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one skeleton, with thecompounds of the present invention. Nevertheless those compounds whichare disclosed in WO 97/16192, WO 97/40035 or WO 99/32481 have differentkinds of functional groups substituting at 1-position of the piperidinering in said skeletal structure, from those in the present invention. Onthe other hand, WO 96/13262 claims compounds with a broad scope ofsubstituents at 1-position of the piperidine ring, which encompass apart of the compounds of the present invention, but the publicationcontains no specific disclosure about the compounds with a spacerbetween the piperidine ring and the nitrogen-containing alicyclicheterocyclic group, which is characteristic of the present invention.

[0009] Moreover, WO 99/32481 or WO 97/40035 contain no disclosure thattheir compounds particularly inhibit M₁ or M₄ receptors with highselectivity. While those compounds described in WO 97/16192 and WO96/13262 are said to exhibit inhibitory activity against muscarinic M₁,M₂ and M₄ receptors but only weak inhibitory action against M₃ receptor,specific compounds or their inhibitory activity are not disclosed atall. Nor there is any disclosure about the compounds′ having selectiveinhibitory action against M₁ and M₄ receptors.

DISCLOSURE OF THE INVENTION

[0010] An objective of the present invention is to provide compoundswhich exhibit selective antagonism at muscarinic receptors M₁ subtypeand/or M₄ subtype, in particular, M4 subtype, which are useful as drugs,and their production processes.

[0011] A further objective of the present invention is to providemuscarinic receptor antagonists and drugs for treating or preventingdiseases or symptoms associated with muscarinic receptors (inparticular, M₁ or M₄ receptors).

[0012] With the view to solve the above problems, we have engaged inconcentrative studies to discover: among a series of compounds having1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one andnitrogen-containing heterocyclic group, a special type ofbenzimidazolone derivatives whose chemical structures are characterizedby the presence of an ethylene group as a spacer between the two groupspossess selective antagonism at M₁ and/or M₄ subtypes, in particular, M₄subtype, of muscarinic receptors. We furthermore discovered that thesecompounds are useful for the prevention and/or treatment of Parkinson'sdisease, drug-induced parkinsonism, dystonia, akinesia, pancreatitis,bilestone/cholecystitis, biliary dyskinesia, achalasia, pain, itch,cholinergic urticaria, irritable bowel syndrome, vomiting, nausea,dizziness, Meniere's disease, motion sickness such as space sickness,sea sickness and car sickness and urinary disturbance. Based on thesediscoveries, we have come to complete the present invention.

[0013] Accordingly, therefore, the present invention relates to:

[0014] 1. benzimidazolone derivatives represented by a general formula[I]

[0015] [in which A ring

[0016] (hereafter this group is referred to as “A ring”) stands for a 5-to 8-membered aliphatic heterocyclic ring containing one nitrogen atom;R¹ binds to the benzene ring, standing for hydrogen, halogen, loweralkyl or lower alkoxy; R² stands for hydrogen or optionallyphenyl-substituted lower alkyl; R^(3a) and R^(3b) stand for hydrogen orR³, R^(3a) standing for hydrogen when R^(3b) stands for R³ and R^(3a)standing for R³ when R^(3b) stands for hydrogen; R³ stands for hydrogen,halogen, hydroxyl, lower alkyl or lower alkenyl, or R³ (i.e., R^(3a) orR^(3b)) and R⁴ together form a 3- to 6-membered carbocyclic ring withthe carbon atoms to which they bind; R⁴ and R⁵ which are the same ordifferent and bind to optional carbon atoms constituting saidheterocyclic ring, stand for hydrogen, halogen, hydroxyl, lower alkyl orlower alkenyl, or R⁴ and R⁵ together form methylene group with thecarbon atoms to which they bind, or R³ (i.e., R^(3a) and R^(3b)) and R⁴together form a 3- to 6-membered carbocyclic ring with the carbon atomsto which they bind, or R⁴ and R⁵ together form a 3- to 6-memberedcarbocyclic ring together with the carbon atoms to which they bind; R⁶stands for aryl or heteroaryl which may have one, two or moresubstituents selected from the group consisting of halogen, cyano,nitro, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl,halogenated lower alkyl, lower alkylamino, di-lower alkylamino, loweralkylthio, lower alkylsulfonyl, optionally fluorine-substituted loweralkoxy, lower acyl, lower acylamino, lower alkoxycarbonyl, carbamoyl,lower alkylcarbamoyl, di-lower alkylcarbamoyl, sulfamoyl, loweralkylsulfamoyl, di-lower alkylsulfamoyl, carbamoyloxy, loweralkylcarbamoyloxy, di-lower alkylcarbamoyloxy, loweralkoxycarbonylamino, sulfamoylamino, (lower alkylsulfamoyl)amino,(di-lower alkylsulfamoyl)amino, (lower alkylsulfamoyl)(loweralkyl)amino, (di-lower alkylsulfamoyl)(lower alkyl)amino, (loweralkylsulfonyl)amino, carbamoylamino, (lower alkylcarbamoyl)amino,(di-lower alkylcarbamoyl)amino and phenoxy; and Z stands for carbonyl(—CO—) or sulfonyl (—SO₂—)] or salts thereof

[0017] 2. benzimidazolone derivatives or salts thereof as described inItem 1, in which the benzimidazolone derivatives represented by thegeneral formula [I] are those of a general formula [I-a]

[0018] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶ and A ring are sameas those in Item 1]:

[0019] 3. benzimidazolone derivatives or salts thereof as described inItem 1, in which the benzimidazolone derivatives represented by thegeneral formula [I] are those of a general formula [I-b]

[0020] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶ and A ring are sameas those in Item 1]:

[0021] 4. benzimidazolone derivatives or salts thereof as described inItem 1, in which the A ring is one selected from the group consisting ofpyrrolidine ring, piperidine ring, perhydroazepine ring,heptamethylenimine ring and 1,2,5,6-tetrahydropyridine ring:

[0022] 5. benzimidazolone derivatives or salts thereof as described inItem 1, in which R⁶ is a group selected from the group consisting ofphenyl, 1-naphthyl, 2-naphthyl, 2-tolyl, 3-tolyl, 4-tolyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3,5-dichlorophenyl, 3-bromophenyl, 2-fluoro-4-chlorophenyl,3-iodophenyl, 4-iodophenyl, 2-(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 2-(dimethylamino)phenyl,3-(dimethylamino)phenyl, 2-cyanophenyl, 3-cyanophenyl,2-(acetamido)phenyl, 3-(acetamido)phenyl, 3-(chloromethyl)phenyl,2-methoxyphenyl, 3-methoxyphenyl, 2-(phenoxy)phenyl, 3-(phenoxy)phenyl,pyrazinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-chloro-3-pyridyl,5-bromo-3-pyridyl, 5-cyano-3-pyridyl, 2-chloro-3-pyridyl,6-chloro-3-pyridyl, 2,3-dichloropyridin-5-yl, 5-methyl-3-pyridyl,2-methoxypyridyl, 2-phenoxypyridyl, 2-(methylthio)pyridyl,2-methylpyridin-5-yl, 3-bromopyridin-5-yl, 2,6-dimethoxypyridyl,2-(propylthio)pyridyl, 2-thienyl, 3-thienyl, 2-quinolyl and 3-quinolyl:

[0023] 6. benzimidazolone derivatives or salts thereof as described inItem 1, in which the benzimidazolone derivative represented by thegeneral formula [I] is

[0024][1-[2-(1-benzoylpiperidin-4-yl)ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0025][1-[2-[1-(4-chlorophenylsulfonyl)piperidin-4-yl]ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0026][1[-[2-[1-[4-(trifluoromethoxy)phenylsulfonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0027][1[-[2-[1-(pyrazinylcarbonyl)piperidin-4-yl]ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0028][1[-[2-[1,2,5,6-tetrahydro-1-(pyrazinylcarbonyl)-4-pyridyl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0029] [1-[2-[1-(pyrazinylcarbonyl)-3-methylene-piperidin-4-yl]ethyl-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0030](S*)-1-[1-[2-[1-(pyrazinylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0031](R*)-1-[1-[2-[1-(pyrazinylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0032](S*)-1-[1-[2-[1-(3-pyridylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0033](R*)-1-[1-[2-[1-(3-pyridylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0034]1-[1l-[2-[1-(pyrazinylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0035][1-[[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0036][1-[[2-[1-(3-chlorobenzoyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0037][1-[[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]-1-methylethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0038]1-[1-[2-hydroxy-2-[4-hydroxy-1-(3-pyridylcarbonyl)piperidin-4-yl]-ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0039]1-[1-[2-[1-(2-chlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0040][1l-[2-[1-(3-chlorobenzoy1)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0041]1-[1-[2-[l-(3-bromobenzoyl)piperidin-4-yl]ethyll-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0042][1-[2-[1-(3-iodobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0043]1-[1-[2-[1-(3,5-dichlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0044]1-[1-[2-[1-(3,4-dichlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0045]1-[1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0046][1-[2-[1-[(5-chloro-3-pyridylcarbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0047] [1-[2-[1-[(4,5-dichloro-3-pyridy1)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0048]1-[1-[2-[1-[(5-bromo-3-pyridy1)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0049]1-[1-[2-[1-(2-thenoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0050][1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,

[0051]1-[1-[2-(1-pyrazinylcarbonylpiperidin-4-y1)ethyl]-piperidin-4-yl]-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,

[0052]1-[1-[2-[1-[(5,6-dichloro-3-pyridyl)carbonyl]-piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0053]1-[1-[2-[1-[(2-propylthio-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0054][1-[2-[4-fluoro-1-(pyrazinylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0055]1-[1-[2-[4-fluoro-1-(3-pyridylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0056] [1[-[(1α, 5α,7β)-3-(pyrazinylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0057] 1-[1[(1α, 5α,7α)-3-(pyrazinylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0058] 1-[1[(1α, 5α,7β)-3-(3-pyridylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0059] 1-[1-[(1α, 5α,7α)-3-(3-pyridylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0060] -[1-[(1α,7α,96)-4-(pyrazinylcarbonyl)-4-azabicyclo[5.3.0]nonan-9-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0061][1-[2-[7-(3-pyridylcarbonyl)-7-azaspiro[3,5]nonan-2-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0062][1-[2-[7-(pyrazinylcarbonyV-7-azaspiro[3,5]nonan-2-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,or

[0063]1-[1-[[6-(3-pyridylcarbonyl)-6-azaspiro[2.5]octan-1-yl]methyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one:

[0064] 7. a method for producing benzimidazolone derivatives representedby the general formula [I]

[0065] [in which R¹ , R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as described in Item 1]or salts thereof, which comprises

[0066] a) a step of reacting a compound represented by a general formula[II]

[0067] [in which R¹ and R² are same as earlier defined] with a compoundrepresented by a general formula [III]

[0068] [in which R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring are same asearlier defined]

[0069] to form a compound represented by a general formula [IV]

[0070] [in which R¹, R² R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as earlier defined] and

[0071] b) a step of reducing (reducing the nitrogen-carbon double bond)the compound of the general formula [IV] as obtained in the step a):

[0072] 8. a method for producing benzimidazolone derivatives representedby the general formula [I]

[0073] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as described in Item 1]

[0074] or salts thereof, which comprises a step of reacting a compoundrepresented by the general formula [II]

[0075] [in which R¹ and R² are same as earlier defined] with a compoundrepresented by the general formula [III]

[0076] [in which R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring are same asearlier defined]

[0077] in the presence of a reagent (reducing agent) which is selectedfrom a group consisting of sodium borohydride, sodium cyanoborohydride,zinc cyanoborohydride and sodium triacetoxyborohydride:

[0078] 9. a method for producing benzimidazolone derivatives representedby the general formula [I]

[0079] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as described in Item 1]

[0080] or salts thereof, which comprises

[0081] a step of reacting a compound represented by a general formula[II]

[0082] [in which R¹ and R² are same as earlier defined] with a compoundrepresented by a general formula [V]

[0083] [in which R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring are same asearlier defined; R⁷ stands for methylsulfonyl, phenylsulfonyl orp-tolylsulfonyl]

[0084] preferably in the presence of a base:

[0085] 10. a method for producing benzimidazolone derivativesrepresented by the general formula [I-a]

[0086] [in which R¹ , R², R^(3a), R^(3b), R⁴, R⁵ and A ring are same asearlier defined]

[0087] or salts thereof which comprises a step of subjecting a compoundof a general formula [VI]

[0088] [in which R¹ , R², R^(3a), R^(3b), R⁴, R⁵ and A ring are same asearlier defined]

[0089] and a carboxylic acid represented by a general formula [VII-a]

R⁶—COOH   [VII-a]

[0090] [in which R⁶ is same as earlier defined]

[0091] or an activated derivative thereof, to a reaction (amidationreaction):

[0092] 11. a method for producing benzimidazolone derivativesrepresented by the general formula [I-b]

[0093] [in which R¹ R², R^(3a), R^(3b) R⁴, R⁵, R⁶ and A ring are same asearlier defined]

[0094] or salts thereof, which comprises a step of subjecting a compoundrepresented by the general formula [VI]

[0095] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵ and A ring are same asearlier defined]

[0096] to a reaction with a sulfonic acid of a general formula [VII-b]

[0097] [in which R⁶ is same as earlier defined]

[0098] or an activated derivative thereof, in the presence or absence ofa base:

[0099] 12. pharmaceutical compositions containing benzimidazolonederivatives represented by the general formula [I]

[0100] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as defined in Item 1]

[0101] or salts thereof, and pharmaceutically acceptable adjuvants:

[0102] 13. muscarinic receptor antagonists which contain benzimidazolonederivatives represented by the general formula [I]

[0103] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as defined in Item 1]

[0104] or salts thereof as the active ingredients: and

[0105] 14. drugs for the treatment and/or prevention of Parkinson'sdisease, drug-induced parkinsonism, dystonia, akinesia, pancreatitis,bilestone/cholecystitis, biliary dyskinesia and achalasia, pain, itch,cholinergic urticaria, irritable bowel syndrome, vomiting, nausea,dizziness, Meniere's disease, motion sickness such as space sickness,sea sickness and car sickness and urinary disturbance, which containbenzimidazolone derivatives represented by the general formula [I]

[0106] [in which R¹ , R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as defined in Item 1]

[0107] or salts thereof as the active ingredients.

[0108] The invention relates further to:

[0109] 15. benzimidazolone derivatives or salts thereof which aredescribed in any one of Items 1-3, in which both R^(3a) and R^(3b) arehydrogen atoms, or either one of R^(3a) and R^(3b) is hydrogen atom andthe other is methyl group;

[0110] 16. benzimidazolone derivatives or salts thereof which aredescribed in any one of Items 1-3, in which R⁶ is a group selected fromthe group consisting of phenyl, 3-chlorophenyl, 4-chlorophenyl,4-(trifluoromethoxy)phenyl, pyrazinyl and 3-pyridyl;

[0111] 17. a method for producing benzimidazolone derivativesrepresented by the general formula [I] or salts thereof, which comprisesa step of reacting a compound of a general formula [XIII]

[0112] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as earlier defined]

[0113] with a compound selected from the group consisting ofcarbonyldiimidazole, triphosgene, diphosgene, methyl chloroformate,ethyl chloroformate, phenyl chloroformate, dimethyl carbonate, diethylcarbonate, S,S-dimethyl dithiocarbonate, S,S-diethyl dithiocarbonate andurea, preferably in the presence of a base;

[0114] 18. a method for producing benzimidazolone derivativesrepresented by the general formula [I] or salts thereof, which comprisesa step of reducing (reducing nitrogen-carbon double bond) compoundsrepresented by the general formula [IV]

[0115] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as earlier defined];

[0116] 19. a method for producing benzimidazolone derivativesrepresented by the general formula [I] or salts thereof, which comprises

[0117] a) a step of reacting a compound of the general formula [II]

[0118] [in which R¹ and R² are same as earlier defined] with a compoundof a general formula [VIII]

[0119] [in which R^(3a), R^(3b), R⁴, R⁵ and A ring are same as earlierdefined, and Y stands for an amino-protective group]

[0120] to form a compound of a general formula [IX]

[0121] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, Y and A ring are sameas earlier defined]

[0122] b) a step of reducing the nitrogen-carbon double bond in thecompound of the general formula [IX] which is obtained in the above stepa), to form a compound of a general formula [X]

[0123] in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, Y and A ring are same asearlier defined]

[0124] c) a step of removing the protective group Y in the compound ofthe general formula [X] which is obtained in the preceding step b) toform a compound of the general formula [VI]

[0125] [in which R¹, R², R^(3a), R^(3b), R⁴, R⁵ and A ring are same asearlier defined] and

[0126] d) a step of subjecting the compound of the general formula [VI]which is obtained in the preceding step c) and a carboxylic acid orsulfonic acid represented by a general formula [VII]

R⁶—Z—OH  [VII]

[0127] [in which R⁶ and Z are same as earlier defined] or theiractivated derivatives to a reaction (amidation reaction);

[0128] 20. a method for producing benzimidazolone derivativesrepresented by the general formula [I] or salts thereof, which comprisessubjecting a compound of the general formula [II]

[0129] [in which R¹ and R² are same as earlier defined] and a compoundof the general formula [XII]

[0130] [in which R³8, R^(3b), R⁴, R⁵, R⁶, Z and A ring are same asearlier defined]

[0131] to condensation reaction in the presence of dialkylazodicarboxylate and an organophosphorus compound such astriarylphosphine or trialkylphosphine;

[0132] 21. Use of benzimidazolone derivatives represented by the generalformula [I] or salts thereof for formulating pharmaceutical compositionsadapted for treating and/or preventing Parkinson's disease, drug-inducedparkinsonism, dystonia, akinesia, pancreatitis, bilestone/cholecystitis,biliary dyskinesia, achalasia, pain, itch, cholinergic urticaria,irritable bowel syndrome, vomiting, nausea, dizziness, Meniere'sdisease, motion sickness and urinary disturbance; and

[0133] 22. methods of treatment and/or prophylaxis of Parkinson'sdisease, drug-induced parkinsonism, dystonia, akinesia, pancreatitis,bilestone/cholecystitis, biliary dyskinesia, achalasia, pain, itch,cholinergic urticaria, irritable bowel syndrome, vomiting, nausea,dizziness, Meniere's disease, motion sickness and urinary disturbance,which methods are characterized by administering to patientsbenzimidazolone derivatives represented by the general formula [I] orsalts thereof.

[0134] Hereinafter the symbols and terms used in this specification areexplained.

[0135] As “halogen”, fluorine, chlorine, bromine and iodine are named,for example.

[0136] As “lower alkyl”, C₁-C₆ linear or branched alkyl can be named forexample, specific examples including methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl,1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl.

[0137] As “lower alkyl which is optionally substituted with phenyl”,those lower alkyl groups as above-named, in which hydrogen atoms atoptional positions are substituted with phenyl can be named for example,specific examples including benzyl, phenethyl and 3-phenylpropyl, inaddition to the above-named specific examples.

[0138] As “lower alkenyl”, for example, C₂-C₆ linear or branched alkenylcan be named, specific examples including vinyl, 1-propenyl, allyl,isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methylallyl,1-methyl-1-propenyl, 1-ethylvinyl, 2-methylallyl, 2-methyl-1-propenyl,3-methyl-2-butenyl and 4-pentenyl.

[0139] As “lower alkynyl”, C₂-C₆ linear or branched alkynyl can be namedfor example, specific examples including ethynyl, 1-propynyl,2-propynyl, 1-methyl-2-propynyl, 1-butynyl, 2-butynyl,1-methyl-2-butynyl, 1-pentynyl and 1-hexynyl.

[0140] As “lower cycloalkyl”, for example, C₃-C₆ cycloalkyl can benamed, specific examples including cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl.

[0141] As “halogenated lower alkyl”, those earlier named lower alkylgroups in which substitutable, optional hydrogen atom(s) are substitutedwith one, two or more, preferably 1-3, halogen atoms, can be named forexample, specific examples including chloromethyl, dichloromethyl,trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,2-chloroethyl, 2,2-dichloroethyl, 2-fluoroethyl, 1,2-difluoroethyl,2,2-difluoroethyl and 2,2,2-trifluoroethyl.

[0142] As “lower alkylamino”, for example, amino which ismono-substituted with said lower alkyl can be named, specific examplesincluding methylamino, ethylamino, propylamino, isopropylamino,butylamino, sec-butylamino and tert-butylamino.

[0143] As “di-lower alkylamino”, for example, amino which isdi-substituted with said lower alkyl can be named, specific examplesincluding dimethylamino, diethylamino, ethylmethylamino, dipropylamino,methylpropylamino and di-isopropylamino.

[0144] As “lower alkylthio”, groups in which sulfur atom binds to saidlower alkyl can be named for example, specific examples includingmethylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio and tert-butylthio.

[0145] As “lower alkylsulfonyl”, sulfonyl substituted with said loweralkyl can be named for example, specific examples includingmethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

[0146] As “lower alkoxy”, groups in which oxygen binds to said loweralkyl, i.e., C₁-C₆ alkoxy groups, can be named for example, specificexample including methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, tert-butoxy and pentyloxy.

[0147] As “optionally fluorine-substituted lower alkoxy”, above alkoxygroups whose substitutable, optional site(s) may be substituted withone, two or more, preferably 1-3, fluorine atoms can be named forexample, specific examples including, in addition to the above-namedalkoxy groups, fluoromethoxy, difluoromethoxy, trifluoromethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.

[0148] As “lower acyl”, C₁-C₆ alkanoyl can be named for example,specific examples including formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl and pivaloyl.

[0149] As “lower acylamino”, amino which is substituted with above loweracyl can be named for example, specific examples including formamido,acetamido, propionylamino, butyrylamino, isobutyrylamino, valerylamino,isovalerylamino and pivaloylamino.

[0150] As “lower alkoxycarbonyl”, carbonyl which is substituted withsaid lower alkoxy, i.e., C₂-C₇ alkoxycarbonyl, can be named for example,specific examples including methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl and pentoxycarbonyl.

[0151] As “lower alkylcarbamoyl”, carbamoyl which is mono-substitutedwith said lower alkyl can be named for example, specific examplesincluding methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,isopropylcarbamoyl, butylcarbamoyl, sec-butylcarbamoyl andtert-butylcarbamoyl.

[0152] As “di-lower alkylcarbamoyl”, carbamoyl which is di-substitutedwith said lower alkyl can be named for example, specific examplesincluding dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl,dipropylcarbamoyl, methylpropylcarbamoyl and diisopropylcarbamoyl.

[0153] As “lower alkylsulfamoyl”, sulfamoyl which is substituted withsaid lower alkyl can be named for example, specific examples includingmethylsulfamoyl, ethylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl,butylsulfamoyl, sec-butylsulfamoyl and tert-butylsulfamoyl.

[0154] As “di-lower alkylsulfamoyl”, sulfonyl binding to said di-loweralkylamino can be named for example, specific examples includingdimethylsulfamoyl, diethylsulfamoyl, ethylmethylsulfamoyl,dipropylsulfamoyl, methylpropylsulfamoyl and diisopropylsulfamoyl.

[0155] As “lower alkylcarbamoyloxy”, oxygen binding to said loweralkylcarbamoyl can be named for example, specific examples includingmethylcarbamoyloxy, ethylcarbamoyloxy, propylcarbamoyloxy,isopropylcarbamoyloxy, butylcarbamoyloxy, sec-butylcarbamoyloxy andtert-butylcarbamoyloxy.

[0156] As “di-lower alkylcarbamoyloxy”, oxygen binding to said di-loweralkylcarbamoyloxy can be named for example, specific examples includingdimethylcarbamoyloxy, diethylcarbamoyloxy, ethylmethylcarbamoyloxy,dipropylcarbamoyloxy, methylpropylcarbamoyloxy anddiisopropylcarbamoyloxy.

[0157] As “lower alkoxycarbonylamino”, amino which is mono-substitutedwith said lower alkoxycarbonyl can be named for example, specificexamples including methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino,isobutoxycarbonylamino, tert-butoxycarbonylamino andpentoxycarbonylamino.

[0158] As “(lower alkylsulfamoyl)amino”, amino which is mono-substitutedwith said lower alkylsulfamoyl can be named for example, specificexamples including (methylsulfamoyl)amino, (ethylsulfamoyl) amino,(propylsulfamoyl) amino, (isopropylsulfamoyl)amino,(butylsulfamoyl)amino, (sec-butylsulfamoyl) amino and(tert-butylsulfamoyl) amino.

[0159] As “(di-lower alkylsulfamoyl)amino”, amino which is substitutedwith said di-lower alkylsulfamoyl can be named for example, specificexamples including (dimethylsulfamoyl)amino, (diethylsulfamoyl)amino,(ethylmethylsulfamoyl)amino, (dipropylsulfamoyl) amino,(methylpropylsulfamoyl) amino and (diisopropylsulfamoyl) amino.

[0160] As “(lower alkylsulfamoyl)(lower alkyl)amino”, amino which issubstituted with said lower alkylsulfamoyl and said lower alkyl can benamed for example, specific examples including (methylsulfamoyl)methylamino and (ethylsulfamoyl) methylamino.

[0161] As “(di-lower alkylsulfamoyl)(lower alkyllamino”, amino which issubstituted with said di-lower alkylsulfamoyl and said lower alkyl canbe named for example, specific examples including(dimethylsulfamoyl)methylamino and (diethylsulfamoyl)methylamino.

[0162] As “(lower alkylsulfonyl)amino”, amino which is mono-substitutedwith said lower alkylsulfonyl can be named for example, specificexamples including methylsulfonylamino, ethylsulfonylamino,propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino,sec-butylsulfonylamino and tert-butylsulfonylamino.

[0163] As “(lower alkylcarbamoyl)amino”, amino which is mono-substitutedwith said lower alkylcarbamoyl can be named for example, specificexamples including (methylcarbamoyl)amino, (ethylcarbamoyl)amino,(propylcarbamoyl)amino, (isopropylcarbamoyl)amino,(butylcarbamoyl)amino, (sec-butylcarbamoyl) amino and(tert-butylcarbamoyl) amino.

[0164] As “(di-lower alkylcarbamoyl)amino”, amino which ismono-substituted with said di-lower alkylcarbamoyl can be named forexample, specific examples including (dimethylcarbamoyl)amino,(diethylcarbamoyl)amino, (ethylmethylcarbamoyl)amino,(dipropylcarbamoyl) amino, (methylpropylcarb amoyl) amino and(diisopropylcarbamoyl)amino.

[0165] Said “salts” of the benzimidazolone derivatives represented bythe general formula [I] signify those customary ones which arepharmaceutically acceptable, and as examples acid addition salts atbasic heterocyclic groups can be named. As such acid addition salts,inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide,sulfate, nitrate, phosphate and perchlorate; organic acid salts such asmaleate, fumarate, tartarate, citrate, ascorbate, benzoate andtrifluoroacetate; and sulfonates such as methanesulfonate, isethionate,benzenesulfonate and p-toluenesulfonate and the like can be named.

[0166] Benzimidazolone derivatives represented bv the general formula[I]

[0167] For disclosing the benzimidazolone derivatives represented by thegeneral formula [I] of the present invention still more specifically,each of those various symbols used in the general formula [I] isexplained in further details, citing specific examples.

[0168] The benzimidazolone derivatives represented by the generalformula [I] in occasions have stereoisomers such as optical isomers,diastereomers or geometrical isomers, depending on the form of thesubstituents therein. The benzimidazolone derivatives represented by thegeneral formula [I] of the present invention cover all of thosestereoisomers and their mixtures.

[0169] Furthermore, where R² is hydrogen, tautomers represented by aformula [I′] to the benzimidazolone derivatives of the general formula[I] can be present, which tautomers or salts thereof also are covered bythe present invention:

[0170] In the present specification, nomination and other explanation ofcompounds of the present invention are given, referring to the positionnumbers on the 2-benzimidazolone skeleton in the compounds of thepresent invention as in the following formula [a]:

[0171] In the benzimidazolone derivatives represented by the generalformula [I], R¹ is, for example, hydrogen, halogen, lower alkyl or loweralkoxy: more specifically, examples of halogen being fluorine, chlorine,bromine and iodine; examples of lower alkyl being methyl, ethyl, propyland isopropyl; and examples of lower alkoxy being methoxy, ethoxy,propoxy and isopropoxy. Of these, hydrogen, fluorine, chlorine andbromine are recommendable.

[0172] The substitution site of R¹ may be any of 4-, 5-, 6- and7-positions on the benzene ring in the benzimidazolone skelton.

[0173] In the benzimidazolone derivatives represented by the generalformula [I], R² is, for example, hydrogen or optionallyphenyl-substituted lower alkyl. More specifically, besides hydrogen,methyl, ethyl, propyl, benzyl and 2-phenylethyl can be named forexample. Preferred R² is hydrogen.

[0174] As examples of such benzimidazolone skeleton [a] containing R¹and R², specifically

[0175] 1,3-dihydro-2H-(benzimidazol-2-one),

[0176] 4-methyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0177] 4-ethyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0178] 4-propyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0179] 4-methoxy-1,3-dihydro-2H-(benzimidazol-2-one),

[0180] 4-ethoxy-1,3-dihydro-2H-(benzimidazol-2-one),

[0181] 4-fluoro-1,3-dihydro-2H-(benzimidazol-2-one),

[0182] 4-chloro-1,3-dihydro-2H-(benzimidazol-2-one),

[0183] 5-methyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0184] 5-ethyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0185] 5-propyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0186] 5-methoxy-1,3-dihydro-2H-(benzimidazol-2-one),

[0187] 5-ethoxy-1,3-dihydro-2H-(benzimidazol-2-one),

[0188] 5-bromo-1,3-dihydro-2H-(benzimidazol-2-one),

[0189] 5-chloro-1,3-dihydro-2H-(benzimidazol-2-one),

[0190] 5-fluoro-1,3-dihydro-2H-(benzimidazol-2-one),

[0191] 6-methyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0192] 6-ethyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0193] 6-propyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0194] 6-methoxy-1,3-dihydro-2H-(benzimidazol-2-one),

[0195] 6-ethoxy-1,3-dihydro-2H-(benzimidazol-2-one),

[0196] 6-chloro-1,3-dihydro-2H-(benzimidazol-2-one),

[0197] 6-fluoro-1,3-dihydro-2H-(benzimidazol-2-one),

[0198] 7-methyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0199] 7-ethyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0200] 7-propyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0201] 7-methoxy-1,3-dihydro-2H-(benzimidazol-2-one),

[0202] 7-ethoxy-1,3-dihydro-2H-(benzimidazol-2-one),

[0203] 7-chloro-1,3-dihydro-2H-(benzimidazol-2-one),

[0204] 7-fluoro-1,3-dihydro-2H-(benzimidazol-2-one),

[0205] 3-methyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0206] and

[0207] 3-benzyl-1,3-dihydro-2H-(benzimidazol-2-one),

[0208] can be named for example, and of these,

[0209] 1,3-dihydro-2H-(benzimidazol-2-one),

[0210] 4-fluoro-1,3-dihydro-2H-(benzimidazol-2-one),

[0211] 5-fluoro-1,3-dihydro-2H-(benzimidazol-2-one),

[0212] 6-fluoro-1,3-dihydro-2H-(benzimidazol-2-one),

[0213] 4-chloro-1,3-dihydro-2H-(benzimidazol-2-one),

[0214] 5-chloro-1,3-dihydro-2H-(benzimidazol-2-one),

[0215] 6-chloro-1,3-dihydro-2H-(benzimidazol-2-one), and

[0216] 5-bromo-1,3-dihydro-2H-(benzimidazol-2-one) are recommendable.

[0217] In the benzimidazolone derivatives represented by the generalformula [II, A ring

[0218] is a 5- to 8-membered aliphatic heterocyclic ring containing onenitrogen atom. More specifically, pyrrolidine ring, piperidine ring,perhydroazepine ring, heptaethylenimine ring, 1,2,3,4-tetrahydropyridinering and 1,2,5,6-tetrahydropyridine ring can be named for example, amongwhich pyrrolidine ring, piperidine ring, perhydrozepine ring,heptamethylenimine ring and 1,2,5,6-tetrahydropyridine ring arepreferred.

[0219] In the benzimidazolone derivatives which are represented by thegeneral formula [I], R^(3a) and R^(3b) stand for hydrogen or R³, R^(3a)standing for hydrogen when R^(3b) stands for R³ and R^(3a) standing forR³ when R^(3b) stands for hydrogen; R³ stands for hydrogen, halogen,hydroxyl, lower (C₁-C₆) alkyl or lower (C₂-C₆) alkenyl; or R³ and R⁴ maytogether form (i.e., R³ and R⁴ link to each other) to form a 3- to6-membered carbocyclic ring, together with the carbon atoms to whichthey bind.

[0220] As specific R³, for example, besides hydrogen and hydroxyl,fluorine, bromine, chlorine, iodine, methyl, ethyl, propyl, isopropyland vinyl may be named, and as the 3- to 6-membered carbocyclic ringformed by R³, R⁴ and the carbon atoms to which they bind, for examplecyclopropane ring, cyclobutane ring, cyclopentane ring and cyclohexanering can be named.

[0221] As preferred R³, hydrogen, fluorine, methyl and ethyl arerecommended, and as the ring which R³ and R⁴ form together with thecarbon atoms to which they bind, cyclopropane ring, cyclopentane ringand cyclohexane ring are recommended.

[0222] In the benzimidazolone derivatives represented by the generalformula [I], R⁴ and R⁵ bind to optional carbon atoms constituting theheterocyclic ring, which may be same or different and stand forhydrogen, hydroxyl, halogen, lower (preferably C₁-C₃) alkyl, lower(preferably C₂-C₃) alkenyl; or R³ and R⁴ may together form (i.e., asbinding to each other) a 3- to 6-membered carbocyclic ring with thecarbon atoms to which they bind; or R⁴ or R⁵ may form, together with thecarbon atom to which they bind, a methylene group (later given r-15); orR⁴ and R⁵ may together form (i.e., as binding to each other) a 3- to6-membered carbocyclic ring, with the carbon atoms to which they bind.

[0223] As specific examples of halogen as R⁴ and R⁵, fluorine, bromine,chlorine and iodine can be named; as the lower alkyl, methyl, ethyl,propyl and isopropyl can be named; and as the lower alkenyl, vinyl,1-propenyl, allyl and isopropenyl can be named.

[0224] Where R³ and R⁴ form a 3- to 6-membered carbocyclic ring togetherwith the carbon atoms to which they bind, as examples of the ring,cyclopropane ring (r-17), cyclobutane ring (r-13), cyclopentane ring(r-6 or r-20) and cyclohexane ring (r-8) can be named.

[0225] Where R⁴ and R⁵ together form a 3- to 6-membered carbocyclic ringwith the carbon atoms to which they bind, as examples of the ringcyclopropane ring (r-19), cyclobutane ring, cyclopentane ring andcyclohexane ring can be named.

[0226] Of these embodiments of the substituents, hydrogen, hydroxyl andfluorine are recommended as preferred R⁴ or R⁵, and the cases wherein R⁴or R⁵ forms methylene group together with the carbon atom to which itbinds are recommended. As the ring which is formed by R³ and R⁴ togetherwith the carbon atoms to which they bind, cyclopropane ring,cyclopentane ring and cyclohexane ring are recommended. Furthermore, asthe ring formed by R⁴ and R¹ together with the carbon atoms to whichthey bind, cyclopropane ring, cyclopentane ring and cyclohexane ring arerecommended.

[0227] As preferred combinations of the aliphatic heterocyclic ringgroups containing R³, R⁴ and R⁵, for example, those having the followingstructures may be named.

[0228] Of the above combinations, structures (r-1), (r-2), (r-4), (r-15)and (r-16) are particularly recommended.

[0229] In the benzimidazolone derivatives represented by the generalformula [I], R⁶ stands for aryl or heteroaryl which may have one, two ormore, preferably 1 or 2, substituents selected from the group consistingof halogen, cyano, nitro, lower alkyl, lower alkenyl, lower alkynyl,lower cycloalkyl, halogenated lower alkyl, lower alkylamino, di-loweralkylamino, lower alkylthio, lower alkylsulfonyl, optionallyfluorine-substituted lower alkoxy, lower acyl, lower acylamino, loweralkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-loweralkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, di-loweralkylsulfamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di-loweralkylcarbamoyloxy, lower alkoxycarbonylamino, sulfamoylamino, (loweralkylsulfamoylamino, (di-lower alkylsulfamoyl)amino, (loweralkylsulfamoyl)(lower alkyl)amino, (di-lower alkylsulfamoyl)(loweralkyl)amino, (lower alkylsulfonyl)amino, carbamoylamino, (loweralkylcarbamoyl)amino, (di-lower alkylcarbamoyl)amino and phenoxy. Wheretwo or more of above substituents bind to aryl or heteroaryl, thesubstituents may be the same or different.

[0230] As the aryl, phenyl, naphthyl and anthryl can be named forexample, and as examples of the heteroaryl, 5- or 6-membered monocyclicheteroaryl containing 1, 2 or more, preferably 1-3, same or differentheteroatoms selected from the group consisting of oxygen, nitrogen andsulfur atoms; or condensed ring heteroaryl formed by condensation ofsaid monocyclic heteroaryl with said aryl or by mutual condensation ofsaid monocyclic heteroaryl groups which may be same or different, can benamed.

[0231] As specific examples of the aryl as R⁶, phenyl, 1-naphthyl,2-naphthyl and 9-anthryl are named, and as the heteroaryl, 2-pyrrolyl,3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-imidazolyl,4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, 5-tetrazolyl,1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]thiphen-2-yl,benzo[b]thiophen-3-yl, 2-benzoimidazolyl, 2-benzoxoxazolyl,3-benzoisoxazolyl, 2-benzothiazolyl, 3-benzoisothiazolyl,1H-benzotriazol-4-yl, lH-indazol-3-yl, 6-purinyl, 8-purinyl, 2-quinolyl,4-quinolyl, 1-isoquinolyl, 4-isoquinolyl, 1-phthaladinyl,4-naphthilidinyl, 2-quinoxalinyl, 5-quinoxalinyl, 4-quinzolinyl,4-cinnolinyl and 4-pteridinyl can be named.

[0232] As the halogen which may substitute on the aryl or heteroaryl,for example, fluorine, chlorine, bromine and iodine can be named.

[0233] As the lower alkyl which may substitute on the aryl orheteroaryl, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl and isopentyl can be named.

[0234] As the lower alkenyl which may substitute on the aryl orheteroaryl, for example, vinyl, 1-propenyl, allyl, isopropenyl,3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-allyl, 1-methyl-1-propenyl,1-ethyl-1-vinyl, 2-methyl-allyl, 2-methyl-1-propenyl, 3-methyl-2-butenyland 4-pentenyl can be named.

[0235] As the lower alkynyl which may substitute on the aryl orheteroaryl, for example, ethynyl, 1-propynyl, 2-propynyl,1-methyl-2-propynyl, 1-butynyl, 2-butynyl, 1-methyl-2-butynyl,1-pentynyl, 3-pentynyl, 4-pentynyl and 1-hexynyl can be named.

[0236] As the lower cycloalkyl which may substitute on the aryl orheteroaryl, for example, cyclopropyl, cyclopentyl and cyclohexyl can benamed.

[0237] The halogenated lower alkyl which may substitute on the aryl orheteroaryl signify lower alkyl substituted with one or more halogenatoms, such as chloromethyl, dichloromethyl, trichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl,dichloroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl and2,2,2-trifluoroethyl.

[0238] As the lower alkylamino which may substitute on the aryl orheteroaryl, for example, methylamino, ethylamino, propylamino,isopropylamino, butylamino, sec-butylamino and tert-butylamino can benamed.

[0239] As the di-lower alkylamino which may substitute on the aryl orheteroaryl, for example, dimethylamino, diethylamino, ethylmethylamino,dipropylamino, methylpropylamino and diisopropylamino can be named.

[0240] As the lower alkylthio which may substitute on the aryl orheteroaryl, for example, methylthio, ethylthio and propylthio can benamed.

[0241] As the lower alkylsulfonyl which may substitute on the aryl orheteroaryl, for example, methylsulfonyl, ethylsulfonyl andpropylsulfonyl can be named.

[0242] As the optionally fluorine-substituted lower alkoxy which maysubstitute on aryl or heteroaryl, for example, methoxy, ethoxy, propoxy,fluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy and2,2,2-trifluoroethoxy can be named.

[0243] As the lower acyl which may substitute on the aryl or heteroaryl,for example, formyl, acetyl, propionyl and butyryl can be named.

[0244] As the lower acylamino which may substitute on the aryl orheteroaryl, for example, formamido, acetamido and propionylamino can benamed.

[0245] As the lower alkoxycarbonyl which may substitute on the aryl orheteroaryl, for example, methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl can be named.

[0246] As the lower alkylcarbamoyl which may substitute on the aryl orheteroaryl, for example, methylcarbamoyl, ethylcarbamoyl andpropylcarbamoyl can be named.

[0247] As the di-lower alkylcarbamoyl which may substitute the aryl orheteroaryl, for example, dimethylcarbamoyl, diethylcarbamoyl anddipropylcarbamoyl can be named.

[0248] As the lower alkylsulfamoyl which may substitute on the aryl orheteroaryl, for example, methylsulfamoyl and ethylsulfamoyl may benamed.

[0249] As the di-lower alkylsulfamoyl which may substitute on the arylor heteroaryl, for example, dimethylsulfamoyl and diethylsulfamoyl canbe named.

[0250] As the lower alkylcarbamoyloxy which may substitute on the arylor heteroaryl, for example, methylcarbamoyloxy can be named.

[0251] As the di-lower alkylcarbamoyloxy which may substitute on thearyl or heteroaryl, for example, dimethylcarbamoyloxy can be named.

[0252] As the lower alkoxycarbonylamino which may substitute on the arylor heteroaryl, for example, methoxycarbonylamino and ethoxycarbonylaminocan be named.

[0253] As the (lower alkylsulfamoylamino which may substitute on thearyl or heteroaryl, for example, (methylsulfamoyl)amino and(ethylsulfamoyl)amino can be named.

[0254] As the (di-lower alkylsulfamoyl)amino which may substitute on thearyl or heteroaryl, for example, (dimethylsulfamoyl)amino and(diethylsulfamoyl)amino can be named.

[0255] As the (lower alkylsulfamoyD)(lower alky1)amino which maysubstitute on the aryl or heteroaryl, for example,(methylsulfamoy)methylamino can be named.

[0256] As the (di-lower alkylsulfamoyl)(lower alkyd)amino which maysubstitute on the aryl or heteroaryl, for example,(dimethylsulfamoyl)methylamino can be named.

[0257] As the (lower alkylsulfonyl)amino which may substitute on thearyl or heteroaryl, for example, methylsulfonylamino, ethylsulfonylaminoand propylsulfonylamino can be named.

[0258] As the (lower alkylcarbamoyl) amino which may substitute on thearyl or heteroaryl, for example, (methylcarbamoyl)amino and(ethylcarbamoyl)amino can be named.

[0259] As the (di-lower alkylcarbamoyl)amino which may substitute on thearyl or heteroaryl, for example, (dimethylcarbamoyl)amino and(diethylcarbamoyl)amino can be named.

[0260] As the aryl or heteroaryl optionally having these varioussubstituents (i.e., R⁶), specifically the following can be named forexample:

[0261] halogenated aryl or heteroaryl such as 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 4-chloro-2-fluorophenyl,2-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl,5-chloro-3-pyridyl, 6-chloro-3-pyridyl, 6-fluoro-3-pyridyl,6-bromo-3-pyridyl, 5,6-dichloro-3-pyridyl and 5-chloro-2-pyrazinyl;

[0262] cyano-containing aryl orheteroaryl such as 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl and 5-cyano-3-pyridyl;

[0263] nitro-containing aryl or heteroaryl such as 2-nitrophenyl,3-nitrophenyl and 4-nitrophenyl;

[0264] aryl or heteroaryl having a lower alkyl substituent such as2-tolyl, 3-tolyl, 4-tolyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl,2-isopropylphenyl, 3-isopropylphenyl, 2-isopropylphenyl,3-isopropylphenyl, 4-isopropylphenyl, 4-methyl-3-pyridyl,5-methyl-3-pyridyl and 5-methyl-2-pyrazinyl;

[0265] aryl or heteroaryl having a lower alkenyl substituent such as2-vinylphenyl, 3-vinylphenyl, 4-vinylphenyl and 5-vinyl-3-pyridyl;

[0266] aryl or heteroaryl having a lower alkynyl substituent such as2-ethynylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 5-ethynyl-3-pyridyl,2-(1-propynyl)phenyl, 3-(1-propynyl)phenyl, 5-(1-propynyl)-3-pyridyl,3-(1-butynyl)phenyl, 5-(1-butynyl)-3-pyridyl and5-(1-hexynyl)-3-pyridyl;

[0267] aryl or heteroaryl having a C₃-C₆ cycloalkyl substituent such as3-cyclopropylphenyl, 3-cyclohexylphenyl and 5-cyclopropyl-3-pyridyl;

[0268] aryl or heteroaryl having a halogenated lower alkyl substituentsuch as 3-(chloromethyl)phenyl, 4-(chloromethyl)phenyl,2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,4-(trifluoromethyl)phenyl, 2-chloro-3-(trifluoromethyl)phenyl and5-(trifluoromethyl)-3-pyridyl;

[0269] aryl or heteroaryl having a lower alkylamino substituent, such as2-(methylamino)phenyl, 3-(methylamino)phenyl, 4-(methylamino)phenyl and2-(methylamino)-3-pyridyl;

[0270] aryl or heteroaryl having a di-lower alkylamino substituent suchas 2-(dimethylamino)phenyl, 3-(dimethylamino)phenyl,4-(dimethylamino)phenyl and 2-(dimethylamino)-3-pyridyl;

[0271] aryl or heteroaryl having a lower alkylthio substituent, such as2-(methylthio)phenyl, 3-(methylthio)phenyl, 4-(methylthio)phenyl,2-(methylthio)-3-pyridyl and 2-(propylthio)-3-pyridyl;

[0272] aryl or heteroaryl having a lower alkylsulfonyl substituent suchas 2-(methylsulfonyl)phenyl, 3-(methylsulfonyl)phenyl,4-(methylsulfonyl)phenyl and 2-(methylsulfonyl)-3-pyridyl;

[0273] aryl or heteroaryl having a lower alkoxy substituent which isoptionally substituted with fluorine, such as 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-(trifluoromethoxy)phenyl,3-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 2-ethoxyphenyl,3-ethoxyphenyl, 4-ethoxyphenyl, 2-methoxy-3-pyridyl,2,6-dimethoxy-3-pyridyl and 5-(trifluoromethoxy)-3-pyridyl;

[0274] aryl or heteroaryl having a lower acyl substituent, such as2-acetylphenyl, 3-acetylphenyl and 4-acetylphenyl;

[0275] aryl or heteroaryl having a lower acylamino substituent such as2-acetamidophenyl, 3-acetamidophenyl and 4-acetamidophenyl;

[0276] aryl or heteroaryl having a lower alkoxycarbonyl substituent suchas 2-(methoxycarbonyl)phenyl, 3-(methoxycarbonyl)phenyl,4-(methoxycarbonyl)phenyl and 5-(methoxycarbonyl)-3-pyridyl;

[0277] aryl or heteroaryl having a carbamoyl substituent, such as2-carbamoylphenyl, 3-carbamoylphenyl, 4-carbamoylphenyl and2-carbamoyl-3-pyridyl.

[0278] aryl or heteroaryl having a lower alkylcarbamoyl substituent suchas 2-(methylcarbamoyl)phenyl, 3-(methylcarbamoyl)phenyl,4-(methylcarbamoyl)phenyl and 2-(methylcarbamoyl)-3-pyridyl;

[0279] aryl or heteroaryl having a di-lower alkylcarbamoyl substituentsuch as 2-(dimethylcarbamoyl)phenyl, 3-(dimethylcarbamoyl)phenyl,4-(dimethylcarbamoyl)phenyl and 2-(dimethylcarbamoyl)-3-pyridyl;

[0280] aryl or heteroaryl having a sulfamoyl group such as2-sulfamoylphenyl, 3-sulfamoylphenyl, 4-sulfamoylphenyl and2-sulfamoyl-3-pyridyl;

[0281] aryl or heteroaryl having a lower alkylsulfamoyl substituent suchas 2-(methylsulfamoyl)phenyl, 3-(methylsulfamoyl)phenyl,4-(methylsulfamoyl)phenyl and 2-(methylsulfamoyl)-3-pyridyl;

[0282] aryl or heteroaryl having a di-lower alkylsulfamoyl substituentsuch as 2-(dimethylsulfamoyl)phenyl, 3-(dimethylsulfamoyl)phenyl,4-(dimethylsulfamoyl)-phenyl and 2-(dimethylsulfamoyl)-3-pyridyl;

[0283] aryl or heteroaryl having a lower alkylcarbamoyloxy substituentsuch as 2-(methylcarbamoyloxy)phenyl, 3-(methylcarbamoyloxy)phenyl and4-(methylcarbamoyloxy)phenyl;

[0284] aryl or heteroacryl having a di-lower alkylcarbamoyloxysubstituent such as 2-(dimethylcarbamoyloxy)phenyl,3-(dimethylcarbamoyloxy)phenyl and 4-(dimethylcarbamoyloxy)phenyl;

[0285] aryl or heteroaryl having a lower alkoxycarbonylamino substituentsuch as 2-(methoxycarbonylamino)phenyl, 3-(methoxycarbonylamino)phenyl,4-(methoxycarbonylamino)phenyl and 2-(methoxycarbonylamino)-3-pyridyl;

[0286] aryl or heteroaryl having a lower alkylsulfamoylamino substituentsuch as 2-(methylsulfamoylamino)phenyl, 3-(methylsulfamoylamino)phenyl,4-(methylsulfamoylamino)phenyl and 2-(methylsulfamoylamino)-3-pyridyl;

[0287] aryl or heteroaryl having a di-lower alkylsulfamoylaminosubstituent such as 2-(dimethylsulfamoylamino)phenyl,3-(dimethylsulfamoylamino)phenyl, 4-(dimethylsulfamoylamino)phenyl;

[0288] aryl or heteroaryl having a (lower alkylsulfamoyl)(loweralkylamino substituent such as 2-[(methylsulfamoyl)methylamino]phenyl,3-[(methylsulfamoyl)methylamino]phenyl and4-[(methylsulfamoyl)methylamino]phenyl;

[0289] aryl or heteroaryl having a (di-lower alkylsulfamoyl)(loweralkyl)amino substituent such as 2-[(dimethylsulfamoylmethylamino]phenyl,3-[(dimethylsulfamoyl)methylamino]phenyl and4-[(dimethylsulfamoyl)methylamino]phenyl;

[0290] aryl or heteroaryl having a lower alkylsulfonylamino substituent,such as 2-(methylsulfonylamino)phenyl, 3-(methylsulfonylamino)phenyl,4-(methylsulfonylamino)phenyl and 2-(methylsulfonylamino)-3-pyridyl;

[0291] aryl or heteroaryl having a lower alkylcarbamoylaminosubstituent, such as 2-(methylcarbamoylamino)phenyl,3-(methylcarbamoylamino)phenyl and 4-(methylcarbamoylamino)phenyl;

[0292] aryl or heteroaryl having a di-lower alkylcarbamoylaminosubstituent, such as 2-(dimethylcarbamoylamino)phenyl,3-(dimethylcarbamoylamino)phenyl and 4-(dimethylcarbamoylamino)phenyl;and

[0293] aryl or heteroaryl having a phenoxy group, such as2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl and2-phenoxy-3-pyridyl.

[0294] Of such examples of R⁶, phenyl, 1-naphthyl, 2-naphthyl, 2-tolyl,3-tolyl, 4-tolyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-bromophenyl, 4-bromophenyl,4-chloro-2-fluorophenyl, 3-iodophenyl, 4-iodophenyl,2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,4-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl,3-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 4-nitrophenyl,2-(dimethylamino)phenyl, 3-(dimethylamino)phenyl, 2-cyanophenyl,3-cyanophenyl, 2-(acetamido)phenyl, 3-(acetamido)phenyl,3-(chloromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,2-(phenoxy)phenyl, 3-(phenoxy)phenyl, pyrazinyl, 5-chloro-2-pyrazinyl,5-methyl-2-pyrazinyi, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-chloro-3-pyridyl, 5-chloro-3- pyridyl, 6-chloro-3-pyridyl,6-fluoro-3-pyridyl, 6-bromo-3-pyridyl,chloro-2-pyridyl,5,6-dichloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl,3-5,6-difluoro-3-pyridyl, 5-cyano-3-pyridyl, 4-methyl-3-pyridyl,5-methyl-3-pyridyl, 5-(trifluoromethyl)-3-pyridyl,5-(1-butynyl)-3-pyridyl, 5-(1-hexynyl)-3-pyridyl, 2-methoxy-3-pyridyl,5-methoxy-3-pyridyl, 2-phenoxy-3-pyridyl, 2-(methylthio)-3-pyridyl,2-methyl-5-pyridyl, 3-bromo-5-pyridyl, 2,6-dimethoxypyridyl,2-(propylthio)-3-pyridyl, 2-thienyl, 3-thienyl, 2-quinolyl, 3-quinolyland 4-quinolyl are preferred.

[0295] Inter alia, phenyl, 3-tolyl, 3-chlorophenyl, 4-chlorophenyl,3-bromophenyl, 3-fluorophenyl, 3-cyanophenyl, 3,5-dichloropheny,4-(trifluoromethoxy)phenyl, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl,5-bromo-3-pyridyl, 5-cyano-3-pyridyl, pyrazinyl and 3-pyridyl arerecommended.

[0296] As examples of specific compounds which are represented by thegeneral formula [I], those of the following structures can be shown, inwhich the compounds having asymmetric carbons are mixtures ofstereoisomers, unless specified otherwise. Structural example 1

As A:

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

[0297] Structural example 2

As A:

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

[0298] Structural example 3

As R⁶:

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

[0299] Structural example 4

As R⁶:

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

[0300] Structural example 5

As B:

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

[0301] Structural example 6

As R⁶:

(71)

(72)

(73)

(74)

[0302] Structural example 7

As A:

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

[0303] Structural example 8

As B:

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

[0304] Structured example 9

As B:

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

[0305] Of the benzimidazolone derivatives represented by the generalformula [I], those preferred are:

[0306][1-[2-(1-benzoylpiperidin-4-yl)ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0307][1-[2-[1-(4-chlorophenylsulfony1)piperidin-4-yl]ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0308][1-[2-[1-[4-(trifluoromethoxy)phenylsulfonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0309]1-[1-[2-[1-(pyrazinylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0310]1-[1-[2-[1,2,5,6-tetrahydro-1-(pyrazinylcarbonyl)-4-pyridyl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0311]1-[1-[2-[1-(pyrazinylcarbonyl)-3-methylene-piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0312](S*)-1-[1-[2-[1-(pyrazinylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0313](R*)-1-[1-[2-[1-(pyrazinylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0314](S*)-1-[1-[2-[1-(3-pyridylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0315](R*)-1-[1-[2-[1-(3-pyridylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0316]1-[1-[2-[1-(pyrazinylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0317]1-[1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0318][1[-[2-[1-(3-chlorobenzoyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0319]1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]-1-methylethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0320]1-[1-[2-hydroxy-2-[4-hydroxy-1-(3-pyridylcarbonyl)piperidin-4-yl]-ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0321]1-[1-[2-[1-(2-chlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0322]1-[1-[2-[1-(3-chlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0323]1-[1-[2-[1-(3-bromobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0324]1-[1-[2-[1-(3-iodobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0325]1[1-[2-[1-(3,5-dichlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0326] 1-[1-[2-[1-(3,4-dichlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0327]1-1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0328]1[1-[2-[1-[(5-chloro-3-pyridy1)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0329]1-[1-[2-[1-[(4,5-dichloro-3-pyridy1)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0330]1-[1-[2-[1-[(5-bromo-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0331]1-[1-[2-[1-(2-thenoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0332]1[1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,

[0333]1-[1-[2-(1-pyrazinylcarbonylpiperidin-4-yl)ethyl]-piperidin-4-yl]-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,

[0334]1-[1-[2-[1-[(5,6-dichloro-3-pyridylcarbonyl]-piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0335]1-[1-[2-[1-[(2-propylthio-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0336]1-[1-[2-[4-fluoro-1-(pyrazinylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0337]1-[1-[2-[4-fluoro-1-(3-pyridylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0338] 1-[1[(1α, 5α,7β)-3-(pyrazinylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0339] 1-[1-[(1α, 5α,7α)-3-(pyrazinylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0340] 1-[1-[(1α, 5α, 7β)-3-(3-pyridylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0341] 1-[1-[(1α, 5α,7α)-3-(3-pyridylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,1-[1-[(1α, 7α, 9β)-4-(pyrazinylcarbonyl)-4-azabicyclo[5.3.0]nonan-9-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0342]1-[1-[2-[7-(3-pyridylcarbonyl)-7-azaspiro[3,5]nonan-2-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

[0343]1[1-[2-[7-(pyrazinylcarbonyl)-7-azaspiro[3.5]nonan-2-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,and

[0344]1-[1-[[6-(3-pyridylcarbonyl)-6-azaspiro[2.5]octan-1-yl]methyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.

[0345] Production methods of the compounds represented bv the generalformula [I]

[0346] Compounds of the present invention can be prepared, for example,by the following production methods 1-5.

[0347] Production method 1

[0348] Production method 1 comprises a two-stage reaction in which amineis condensed with aldehyde or ketone, and either successively orsimultaneously reduced (hereafter it is occasionally referred to as“reductive alkylation”), the scheme being as illustrated by thefollowing formulae.

[0349] in which R¹ , R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring aresame as earlier defined.

[0350] The process comprises, as specific steps,

[0351] 1a) a step of reacting (condensing) a compound of the generalformula [II] with a compound of the general formula [III], to form acompound of the general formula [IV], and

[0352] 1b) a step of reducing (reducing the nitrogen-carbon double bond)the compound of the general formula [IV] which is obtained in the step1a).

[0353] This reaction constitutes a method preferred in the cases whereR^(3a) and R^(3b) are hydrogen or lower alkyl, or R³ (R^(3a) or R^(3b))and R⁴ form, together with the carbons to which they bind, a 3- to6-membered carbocyclic ring.

[0354] In the occasion of said reaction, functional group(s) notparticipating in the reaction, where present, can be protected duringthe series of the reactions where necessary, and deprotected after thereduction.

[0355] As such functional groups, for example, amine, ketone, aldehyde,alcohol and the like can be named. As protective groups of amine,aralkyl such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, benzhydryl and trityl; C₁-C₆ alkanoyl suchas formyl, acetyl, propionyl, butyryl and pivaloyl; arylalkanoyl such asbenzoyl, phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl andtert-butoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl,p-nitrobenzyloxycarbonyl and phenethyloxycarbonyl; trialkylsilyl such astrimethylsilyl and tert-butyldimethylsilyl; and phthaloyl are named, inparticular, tert-butoxycarbonyl and benzyloxycarbonyl being preferred.

[0356] Also as protective groups of ketone or aldehyde, acetals andketals such as ethyleneacetal, trimethyleneacetal, ethyleneketal andtrimethyleneketal are named.

[0357] As protective groups of alcohol, trialkylsilyl such astrimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl;lower alkoxymethyl such as methoxymethyl and 2-methoxyethoxymethyl;tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl such as benzyl,p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl andtrityl; and acyl such as formyl and acetyl are named, in particular,methoxymethyl, tetrahydropyranyl, trityl, trimethylsilylethoxymethyl,tert-butyldimethylsilyl and acetyl being preferred.

[0358] Method for introduction/removal of the protective group(s)differs depending on the kind of the protective group and stability ofobtained compound. Whereas, for example, those methods described inliterature [cf. Protective Groups in Organic Synthesis, T. W. Greene,John Wiley & Sons Co. (1981)] or methods analogous thereto can befollowed to conduct the introduction/removal.

[0359] Step 1a)

[0360] The reaction of step 1a) is conducted by mixing a compound of thegeneral formula [II] with a compound of the general formula [III] inreaction solvent. Where necessary, the reaction can be conducted in thepresence of a desiccant such as anhydrous magnesium sulfate, anhydroussodium sulfate or the like, or using Dean-Stark desiccator.

[0361] As the use rates of the compounds of the general formulae [II]and [III], 0.5-5.0 moles, preferably 1.1-2.0 moles, of the compound ofthe general formula [III] is used per mole of the compound of thegeneral formula [II].

[0362] As the reaction solvent, for example, alcohols such as methanol,ethanol, propanol and 2-propanol; ethers such as ethyl ether,tetrahydrofuran and 1,4-dioxane; esters such as ethyl acetate;halogenated hydrocarbons such as methylene chloride, chloroform and1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene,chlorobenzene and xylene; aprotic polar solvents such asN,N-dimethylformamide, acetonitrile and hexamethylphosphoric triamide;or mixed solvents of the foregoing can be named.

[0363] As the reaction temperature, for example it can be 0-150° C.,preferably 10-110° C., and the reaction terminates in 5 minutes -48hours.

[0364] After termination of the step 1a) reaction, the compound of thegeneral formula [IV] may be isolated, purified and then subjected to thestep 1b), or the step 1b) can be conducted using the reaction liquidcontaining the compound of the general formula [IV] which is obtainedfrom the step 1a) reaction as it is, or the step 1a) and step 1b) may beconducted simultaneously.

[0365] In particular, compounds of the general formula [IV] may haveunstable structures difficult of isolation, depending on the kinds ofthe substituents (R¹-R⁶). In such a case, it is preferred to conduct thestep 1b) without isolation and purification, or to conduct the steps 1a)and 1b) simultaneously.

[0366] Step 1b)

[0367] By reducing the nitrogen-carbon double bond in the compound ofthe general formula [IV] as obtained in the step 1a), a benzimidazolonederivative of the general formula [I] is obtained.

[0368] As a method of the reduction, for example, reduction using ametal hydride compound or hydrogenation using hydrogen gas in thepresence of a metal catalyst can be adopted. As useful metal hydridecompound, for example, lithium borohydride, sodium borohydride, zinccyanoborohydride, sodium cyanoborohydride and sodiumtriacetoxyborohydride can be named. In particular, where such a reducingagent as sodium borohydride, sodium cyanoborohydride, zinccyanoborohydride or sodium triacetoxyborohydride, which preferentiallyreduces imine/enamine, is used, benzimidazolone derivatives representedby the general formula [I] can be obtained in single step, by conductingthe reaction of the step 1a) in the presence of such a reducing agent.

[0369] Where a metal hydride complex is used as the reducing agent, theuse rate of the reducing agent is normally 0.25-30 moles, preferably1.5-10 moles, per mole of the compound of the general formula [IV] or[II].

[0370] Exemplary reaction temperature ranges −20-100° C., preferably0-50° C., and the reaction terminates normally in 1-24 hours.

[0371] In the hydrogenation method by contacting hydrogen gas in thepresence of a metal catalyst, known metal catalyst, e.g.,palladium-carbon, Raney nickel, palladium hydroxide-carbon and the likecan be used. Its use rate is normally 0.01-1000 wt parts, preferably1.0-50 wt parts, per 100 wt parts of the compound of the general formula[IV].

[0372] Exemplary hydrogen pressure in the hydrogenation reaction rangesfrom ambient pressure to 5 atmospheres; exemplary reaction temperatureranges 0-100° C., preferably 10-50° C.; and the reaction terminatesnormally in 5 minutes −24 hours.

[0373] In said reducing reaction, solvent may be suitably used dependingon the kind of reducing agent and form of reaction, examples of usefulsolvent including alcohols such as methanol, ethanol, isopropyl alcoholand tert-butyl alcohol; ethers such as diethyl ether, diisopropyl ether,dibutyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran anddiglyme; esters such as ethyl acetate; aliphatic hydrocarbons such aspentane, hexane, heptane and cyclohexane; aromatic hydrocarbons such asbenzene and toluene; inert solvent such as water; and mixed solvents ofthe foregoing.

[0374] As compounds of the general formula [II], these which arecommercially available can be used. They can furthermore be easilyprepared following the methods described in, e.g., InternationalPublication WO 96/13262.

[0375] As specific examples of the compound represented by the generalformula [II],

[0376] 1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0377] 4-methyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0378] 4-ethyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0379] 4-propyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0380] 4-methoxy-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0381] 4-ethoxy-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0382] 4-fluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0383] 4-chloro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0384] 5-methyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0385] 5-ethyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0386] 5-propyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0387] 5-methoxy-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0388] 5-ethoxy-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0389] 5-chloro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0390] 5-fluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0391] 6-methyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0392] 6-ethyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0393] 6-propyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0394] 6-methoxy-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0395] 6-ethoxy-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0396] 6-chloro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0397] 6-fluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0398] 7-methyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0399] 7-ethyl-1-(piperidin-4-y)-1,3-dihydro-2H-benzimidazol-2-one,

[0400] 7-propyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0401] 7-methoxy-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0402] 7-ethoxy-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0403] 7-chloro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0404] 7-fluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,

[0405] 3-methyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,and

[0406] 3-benzyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one canbe named.

[0407] Compounds represented by the general formula [III] can beprepared, for example, by the following methods.

[0408] Production method of compounds represented bv the general formula[III]

[0409] Compound 1 is oxidized to form compound 2. The oxidation isconducted by known methods, using oxidizing agent such as pyridiniumchlorochromate, chromium trioxide, pyridinium dichromate, mangagesedioxide, sulfur trioxide-pyridine complex, oxalylchloride/dimethylsulfoxide and the like. In that occasion, the amine maybe protected by a protective group in advance of the oxidation, andlater the protective group may be removed. Then the compound 2 isreacted with carboxylic acid or sulfonic acid represented by the generalformula [VII] in the manner following the later described step 2d), toform a compound represented by the general formula [III].

[0410] It is also possible to react compound 1 with the carboxylic acidor sulfonic acid of the general formula [VII] to form a compound of ageneral formula [XII], and to form a compound of the general formula[III] by oxidizing thus formed compound of the formula [XII]. As thereaction conditions, those earlier described can be used.

[0411] As examples of compound 1, piperidine-4-ethanol,3-methylene-piperidine-4-ethanol, 1,2,5,6-tetrahydropyridine-4-ethanol,2-(perhydroazepin-4-yl)ethanol, 2-(piperidin-4-yl)-1-propanol,1-(piperidin-4-yl)-2-propanol, 3-azabicyclo[3.3.0]octan-7-ol and7-azaspiro[3,5]nonan-2-ol can be named. Commercial products of thesecompounds can be used, or they can be prepared by known methods ofsynthesis or following the methods as described in production examplesgiven later.

[0412] Production method 2

[0413] Production method 2 comprises a 4-stage reaction, whose scheme isshown by the following formulae.

[0414] In the above formulae, Y stands for amino-protective group; R¹,R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring are same as earlierdefined.

[0415] As the specific steps:

[0416] 2a) a step of reacting a compound of the general formula [II]with a compound of the general formula [VIII] to form a compound of thegeneral formula [IX];

[0417] 2b) a step of reducing the nitrogen-carbon double bond in thecompound of the general formula [IX] as obtained in the step 2a) to forma compound of the general formula [X];

[0418] 2c) a step of removing the protective group Y in the compound ofthe general formula [X] as obtained in the step 2b) to form a compoundof the general formula [VI]; and

[0419] 2d) a step of reacting (amidating) the compound of the generalformula [VI] as obtained in the step 2c) with carboxylic acid orsulfonic acid of the general formula [VII],

R⁶—Z—OH   [VII]

[0420] or activated derivative thereof to form a compound of the generalformula [I].

[0421] Said reactions constitute a production method particularlyfavorable where R^(3a) and R^(3b) are hydrogen or lower alkyl, or R³(R^(3a) or R^(3b)) and R⁴ together form a 3- to 6-membered carbocyclicring, in combination with the carbon atoms to which they bind.

[0422] In the compounds represented by the general formula [VIII], asthe amino-protective group Y, for example, aralkyl such as benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,benzhydryl and trityl; C₁-C₆ alkanoyl such as formyl; arylalkanoyl suchas phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl,trichloroethyloxycarbonyl, trimethylsilylethyloxycarbonyl and9-fluorenylmethyloxycarbonyl; and aralkyloxycarbonyl such asbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and phenethyloxycarbonyl canbe named, among which benzyloxycarbonyl and tert-butoxycarbonyl beingparticularly recommendable.

[0423] Step 2a)

[0424] The reaction of a compound of the general formula [II] with acompound of the general formula [VIII] is conducted under the reactionconditions following those for the step 1a) of the production method 1,to form a compound of the general formula [IX].

[0425] Step 2b)

[0426] The compound of the general formula [IX] as obtained in the step2a) is reduced as in the step 1b) in the production method 1 to form acompound represented by the general formula [XI.

[0427] Step 2c)

[0428] The protective group Y in the compound of the general formula [X]as obtained in the step 2b) is removed to provide an amine [VI].

[0429] Methods of removing the protective group Y differ depending onthe kind of said group and stability of individual object compound [I].The removal is conducted following those methods, for example, describedin literature [Protective Groups in Organic Synthesis, T. W. Greene,John Wiley & Sons (1981)] or methods analogous thereto, by solvolysisusing acid or base (e.g. hydrolysis using from 0.01 mole to large excessof an acid, preferably trifluoroacetic acid, formic acid, hydrochloricacid or the like; hydrolysis using from equimolar to large excess of abase, preferably potassium hydroxide, calcium hydroxide or the like);chemical reduction using metal hydride complex, or hydrogenolysis(catalytic reduction) using palladium-carbon catalyst, palladiumhydroxide, Raney nickel catalyst, and the like.

[0430] More specifically, aralkyl such as benzyl, p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and tritylare removed by catalytic reduction; C₁-C₆ alkanoyl such as formyl andpivaloyl are removed with hydrochloric acid, hydrazine or the like;benzoyl or the like are removed with potassium hydroxide solution; loweralkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyland tert-butoxycarbonyl are removed with hydrochloric acid,trifluoroacetic acid and the like; and aralkyloxycarbonyl such asbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and phenethyloxycarbonyl areremoved by catalytic reduction.

[0431] Step 2d)

[0432] This is an amidation reaction of the compound as obtained in thestep 2c) with carboxylic acid or sulfonic acid of the general formula[VII]

R⁶—Z—OH [VII]

[0433] or activated derivative thereof, to form a benzimidazolonederivative represented by the general formula [I]. The carboxylic acidor sulfonic acid represented by the general formula [VII] may be thosewhich are commercially available, or they can be readily prepared by themethods described in Organic Functional Group Preparations, 2nd edition,S. R. Sandler, Academic Press (1983), etc.

[0434] In this production method, the four stages of the reaction usinga compound of the general formula [II] as the starting material can becontinuously conducted, or the method may be started from the step 2b),step 2c) or step 2d), using as the starting materials, respectively, aseparately synthesized compound of the general formula [IX], aseparately synthesized compound of the general formula [X] or aseparately synthesized compound of the general formula [VI].

[0435] Where the compound of the general formula [VII] is a carboxylicacid, as its activated derivatives, those known per se can be used, forexample, anhydride of the carboxylic acid, anhydride mixture of thecarboxylic acid with other acid(s), carboxylic acid lower alkyl ester,acyl halide derived from the carboxylic acid, thiol ester of thecarboxylic acid (i.e., S-alkyl ester of thiocarboxylic acid) oractivated ester of the carboxylic acid.

[0436] As the mixed acid anhydride of the carboxylic acid with otheracid(s), for example, those of the carboxylic acid and ethylmonocarbonate or isobutyl monocarbonate can be named, and as examples ofthe carboxylic acid lower alkyl ester, methyl ester, ethyl ester, etc.of the carboxylic acid can be named.

[0437] As the carboxylic acid-derived acyl halide, for example, acylchloride, acyl bromide and the like can be named.

[0438] As S-alkyl ester of thiocarboxylic acid, for example, S-methylester, S-ethyl ester, S-tert-butyl ester, S-phenyl ester andS-(2-pyridyl) ester of thiocarboxylic acid can be named.

[0439] S-alkyl esters of thiocarboxylic acid can be prepared following,for example, those methods as described in Chem. Lett., 1981, p. 133 orHeterocycles, Vol.33, pp.131-134 (1992), using corresponding carboxylicacids as the starting materials.

[0440] As activated esters of carboxylic acid, for example, esters ofcarboxylic acid with phenols such as 2,4,5-trichlorophenol,pentachlorophenol, pentafluorophenol, 2-nitrophenol and 4-nitrophenol;or with hydroxyl derivatives such as N-hydroxysuccinimide,1-hydroxybenztriazole, N-hydroxypiperidine,N-hydroxy-5-norbornene-2,3-dicarboxyimide and N-hydroxyphthalimide canbe named. These activated esters can be obtained through esterificationof carboxylic acid with hydroxyl derivatives, in the presence ofcondensing agent such as dicyclohexyl carbodiimide,1-ethyl-3-(3-(dimethylamino)propy1)carbodiimide or the like.

[0441] As such activated carboxylic acid derivatives, those which arecommercially available can be used, or they can be prepared from thecarboxylic acid by known methods (e.g., “Fundamentals and Experiments ofPeptide Synthesis” Nobuo IZUMIYA, et al., Maruzen Co., 1983).

[0442] As specific examples of the carboxylic acid represented by thegeneral formula [VII], benzoic acid, 2-chlorobenzoic acid,3-chlorobenzoic acid, 3-bromobenzoic acid, 3-iodobenzoic acid,3-methoxybenzoic acid, 3-trifluoromethylbenzoic acid,3-chloromethylbenzoic acid, 3-acetamidobenzoic acid,3-dimethylaminobenzoic acid, 3-cyanobenzoic acid, 3-benzoylbenzoic acid,4-chlorobenzoic acid, 4-iodobenzoic acid, 3,4-dichlorobenzoic acid,3,5-dichlorobenzoic acid, 2-fluoro-4-chlorobenzoic acid,2-pyridinecarboxylic acid, 3-pyridinecarboxylic acid (nicotinic acid),2-chloropyridine-3-carboxylic acid, 2-thiomethylpyridine-3-carboxylicacid, 2-thiopropylpyridine-3-carboxylic acid,2-methoxypyridine-3-carboxylic acid, 5-chloropyridine-3-carboxylic acid,5-bromopyridine-3-carboxylic acid, 4-methylpyridine-3-carboxylic acid,5-methylpyridine-3-carboxylic acid, 6-methylpyridine-3-carboxylic acid,3-pyridinecarboxylic acid, 5,6-dichloropyridine-3-carboxylic acid,2-phonoxypyridine-3-carboxylic acid, 4-pyridinecarboxylic acid,2-chloropyridine-4-carboxylic acid, thiophene-2-carboxylic acid,naphthalene-1-carboxylic acid and the like can be named. Of those,preferably 3-pyridinecarboxylic acid and pyrazinecarboxylic acid arerecommended.

[0443] When the compound represented by the general formula [VII] issulfonic acid, its activated derivatives heretofore known can be used,e.g., anhydride and lower alkyl ester of the sulfonic acid; sulfonylhalide and sulfonyl azide derived from the sulfonic acid; and the like.

[0444] As examples of lower alkyl ester of the sulfonic acid, sulfonicacid methyl ester, sulfonic acid ethyl ester and the like can be named.

[0445] As examples of sulfonyl halide derived from the sulfonic acid,sulfonyl chloride, sulfonyl bromide and sulfonyl fluoride can be named.

[0446] As specific examples of the sulfonic acid represented by thegeneral formula [VII], benzenesulfonic acid, 4-chlorobenzenesulfonicacid, 4-bromobenzenesulfonic acid, 4-nitrobenzenesulfonic acid,4-trifluorobenzenesulfonic acid, 4-trifluoromethoxybenzenesulfonic acid,1-naphthalenesulfonic acid, p-toluenesulfonic acid, xylenesulfonic acidand mesitylenesulfonic acid can be named. Of those, preferablybenzenesulfonic acid, 4-chlorobenzenesulfonic acid and4-trifluoromethoxybenzenesulfonic acid are recommended.

[0447] As these activated derivatives, those which are commerciallyavailable can be used, or they can be prepared by the methods describedin, for example, Organic Functional Group Preparations, 2nd ed., S. R.Sandler, Academic Press (1983).

[0448] The amidation reaction between the carboxylic acid, sulfonic acidor activated derivatives thereof and the amine represented by thegeneral formula [VI] is conducted under heretofore known reactionconditions.

[0449] Amidation of the carboxylic acid or activated derivatives thereof

[0450] Where such a carboxylic acid is used in the amidation reaction,the reaction is preferably carried out in the presence of a condensingagent such as carbonyldlimidazole, 1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide,diphenylphosphorylazide, dipyridyldisulfide-triphenylphosphine and thelike, in particular, 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide.

[0451] Where a carboxylic acid of the general formula [VII] is used inthe amidation reaction, the use rates of the carboxylic acid and amineare: 0.5-2 moles, preferably 0.6-1.0 mole, of the amine of the generalformula [VI] is used per mole of the carboxylic acid of the generalformula [VII].

[0452] While the use rate of said condensing agent is not strictlylimited, it is normally used in a range of 1-3 moles, preferably 1.0-1.5moles, per mole of the carboxylic acid of the general formula [VII].

[0453] The reaction is normally conducted in an inert solvent, such asdiethyl ether, tetrahydrofuran, N,N-dimethylformamide, dioxane, benzene,toluene, chlorobenzene, methylene chloride, chloroform, carbontetrachloride, 1,2-dichloroethane, trichloroethylene and the like andmixtures of these solvents. Of these, tetrahydrofuran,N,N-dimethylformamide, 1,4-dioxane, chloroform and methylene chlorideare preferred.

[0454] The reaction temperature can normally be within a range of 0-150°C., preferably 10-60° C., and the reaction normally terminates in 5minutes—two days.

[0455] The above reaction can be performed in the presence of a base, tosmoothly advance the reaction. As the base, those preferred are, forexample, inorganic base such as calcium hydroxide, sodium carbonate,potassium carbonate and sodium hydrogencarbonate; or organic base suchas triethylamine, ethyldiisopropylamine, pyridine,4-(dimethylamino)pyridine and N,N-dimethylaniline. When a base is used,its use rate is, for example, within a range of 0.05-10 moles,preferably 0.05-5 moles, per mole of the carboxylic acid of the generalformula [VII] or activated derivative thereof.

[0456] Whereas, when an activated derivative of the carboxylic acid isused in the amidation reaction, the use rates of the activatedderivative of the carboxylic acid and an amine of the general formula[VI] are: 0.5-2 moles, preferably 1.0-1.2 moles, of the activatedderivative per mole of the amine of the general formula [VI].

[0457] The reaction is normally conducted in an inert solvent such as,for example, halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride, 1,2-dichloroethane andtrichloroethylene; ethers such as ethyl ether, tetrahydrofuran and1,4-dioxane; esters such as ethyl acetate; aromatic hydrocarbons such asbenzene, toluene, chlorobenzene and xylene; aprotic polar solvents suchas N,N-dimethylformamide, acetonitrile, acetone and hexamethylphosphorictriamide; or mixed solvents of the foregoing.

[0458] As the reaction temperature, −70-150° C., preferably −20-100° C.,can be used for example, and the reaction terminates normally within 5minutes -2 days. Again, the reaction can be conducted in the presence ofa base for smooth progress.

[0459] As the kind and use rate of the base, the earlier specified canbe applied.

[0460] When a lower alkyl ester of carboxylic acid or an S-alkyl esterof thiocarboxylic acid is used as the carboxylic acid derivative, thereaction temperature can be made 20-180° C., and the reaction pressure,1-200 atmospheres.

[0461] Amidation of sulfonic acid or its activated derivative

[0462] Where sulfonic acid is used in the reaction, it is desirable toactivate it in advance by the means known per se, using an activatingagent such as phosphorus pentachloride, phosphoryl chloride,chlorosulfuric acid, thionyl chloride and the like.

[0463] Where an activated derivative of sulfonic acid is used in thereaction, use rates of the derivative and the amine of the generalformula [VI] are: 0.5-2 moles, preferably 1.0-1.2 moles, of theactivated derivative of the sulfonic acid of the general formula [VII]per mole of the amine of the general formula [VI].

[0464] The reaction is normally conducted in an inert solvent. As theinert solvent, those customarily used in the occasions of amidatingcarboxylic acid can similarly be used. The reaction temperatures can bein the range of, for example, −70-150° C., preferably −20-100° C., andnormally the reaction terminates within 5 minutes—a day. The reactioncan be performed in the presence of a base, to smooth its progress.

[0465] The kind and use rate of the base are similar to those asdescribed as to the amidation of the carboxylic acid.

[0466] Where a lower alkyl ester of the sulfonic acid is used as thesulfonic acid derivative, a benzimidazolone derivative of the generalformula [I] can be obtained by conducting the reaction at temperaturesranging 20-180° C. and pressures of 1-200 atmospheres.

[0467] Those compounds represented by the general formula [X] can beprepared, for example, by the following methods besides the one via theabove steps 2a) and 2b).

[0468] Methods of producing the compounds which are represented by thegeneral formula [X]

[0469] B-1

[0470] This reaction uses as the starting material compounds [VIII]instead of those represented by the general formula [III] used in theproduction method 1, and the reaction conditions same as described as tothe production method 1 can be used. Said compounds [VIII] are obtainedby protecting the amine in the compound 2 with an amino-protective groupY.

[0471] B-2

[0472] This reaction uses as the starting material compounds representedby a later described general formula [XII′] instead of the compounds ofthe general formula [XII] used in the later described production method4, and the reaction conditions same as described as to the productionmethod 4 can be used. Said compounds of the general formula [XII′] areobtained by protecting the amine in the compound 1 with a protectivegroup Y.

[0473] B-3

[0474] This reaction uses as the starting material the compound 6instead of the compounds represented by the general formula [XI] used inthe later described production method 3, and the reaction conditionssame as described as to the production method 3 can be used. Moreover,the compound 6 can be prepared following the preparation process of thecompounds of the general formula [XI] as described in the productionmethod 3.

[0475] The compound 7 obtained through the methods B-1 to B-3 can beconverted to, where necessary, the corresponding compound of the generalformula [X], as alkylated by a means known per se, using lower alkylhalide optionally having phenyl substituent, or alkyl methanesulfonateoptionally having phenyl substituent on its alkyl group.

[0476] Production method 3

[0477] Production method 3 is one for reacting a compound of the generalformula [II] with a compound of the general formula [XI] by a scheme asin the following.

[0478] In the formula, X stands for a leaving group. R¹, R², R^(3a),R^(3b), R⁴, R⁵, R⁶, Z and A ring have the earlier given significations.

[0479] This reaction is characterized by subjecting a compound of thegeneral formula [II] and a compound of the general formula [XI] toN-alkylation reaction in the optional but preferred presence of base.

[0480] Specific examples of the leaving group X in the above formulainclude halogen such as chlorine, bromine and iodine; organosulfonyloxysuch as methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxyand p-tolylsulfonyloxy; and 1-imidazolyl and the like. Of those,methylsulfonyloxy, phenylsulfonyloxy or p-tolylsulfonyloxy are preferredas the X.

[0481] The use rates of the compound of the general formula [II] andthat of the general formula [XI] are 0.8-1.5 moles, preferably 0.95-1.2moles, of the compound of the general formula [XI] per mole of thecompound of the general formula [II]. The reaction is carried out in aninert solvent having no detrimental effect on the reaction.

[0482] As such an inert solvent, ether such as tetrahydrofuran or1,4-dioxane; halogenated hydrocarbon such as methylene chloride orchloroform; and aprotic polar solvent such as N,N-dimethylformamide,N,N-dimethylacetamide or acetonitrile can be named for example.

[0483] The reaction is preferably conducted in the presence of a base.Examples of the base include organic bases such as triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine and lithiumdiisopropylamide; and inorganic bases such as sodium hydride, sodiumhydroxide, sodium carbonate, potassium carbonate and sodiumhydrogencarbonate.

[0484] The use rate of the base is, for example, 1-5 moles, preferably1.0-3.0 moles, of the base per mole of the compound of the generalformula [II].

[0485] The reaction temperature normally is within a range of −78-150°C., preferably 0-80° C., and the reaction normally terminates in 5minutes -7days, preferably 30 minutes -24 hours.

[0486] Compounds of the general formula [XI] can be easily prepared byreacting a compound of the general formula [XII] with a halogenatingagent such as thionyl chloride, phosphorus trichloride, phosphoruspentachloride, phosphorus oxychloride, oxalyl chloride, phosgene,thionyl bromide, phosphorus tribromide or phosphorus pentabromide,carbon tetrabromide-triphenylphosphine and the like; or by reacting acompound of the general formula [XII] with methanesulfonyl chloride,trifluoromethanesulfonic anhydride, benzenesulfonyl chloride orp-tolenesulfonyl chloride, in the presence of a base by the method knownper se.

[0487] Production method 4

[0488] Production method 4 is for producing a benzimidazolone derivativeof the general formula [I], through a condensation reaction of acompound of the general formula [II] with a compound of the generalformula [XII], in the presence of dialkylazodicarboxylate and an organicphosphorus compound such as triarylphosphine or trialkylphosphine.

[0489] This method is particularly advantageous where R^(3a) is loweralkyl or lower alkenyl, or R^(3a) and R⁴ together form a 3- to6-membered carbocyclic ring. The reaction scheme is as follows.

[0490] in the above formulae, R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z andA ring are same as earlier defined.

[0491] Examples of dialkylazodicarboxylate useful in the productionmethod 4 include diethylazodicarboxylate, diisopropylazodicarboxyate,diisobutylazodicarboxylate, di-tert-butylazodicarboxylate and the like.

[0492] As examples of triarylphosphine, triphenyphophine,tri(o-tolyl)phosphine and the like can be named, and astrialkylphosphine, triethylphosphine, tributylphosphine,trioctylphosphine and the like can be named. In particular, combinationsof diisopropylazodicarboxylate or diisobutylazodicarboxylate withtributylphosphine are recommended.

[0493] As the use rate of the compound of the general formula [II] andthat of the general formula [XII], for example, 1-3 moles, preferably1.0-1.5 moles, of the compound of the general formula [XII] is used permole of the compound of the general formula [II].

[0494] As the use rates of dialkylazodicarboxylate and theorganophosphorus compound such as triarylphosphine or trialkylphosphine,1-3 moles, preferably 1-1.5 moles of dialkylazodicarboxylate and 1-3moles, preferably 1.0-1.5 moles of the organophosphorus compound can beused per mole of the compound of the general formula [II].

[0495] As the reaction solvent, halogenated hydrocarbons such asmethylene chloride, chloroform and 1,2-dichloroethane; aliphatichydrocarbons such as heptane and hexane; ethers such as diethyl ether,tetrahydrofuran and 1,4-dioxane; esters such as ethyl acetate and methylacetate; and aprotic polar solvents such as N,N-dimethylformamide anddimethyl sulfoxide can be named for example.

[0496] The reaction temperatures can range, for example, 0-150° C.,preferably 0-80° C., and the reaction normally terminates in 2-24 hours.

[0497] A compound of the general formula [XII] can be obtained, as shownin the production method 1, by reacting a compound 1 with that of ageneral formula [VII], in the manner following the production method2d).

[0498] Furthermore, the compound of the general formula [XIII in theproduction method 4 can be replaced by that of a general formula [XII′]

[0499] which is reacted in the similar manner to produce a correspondingcompound of the general formula [XI. This compound can be reacted in themanner following the production method 3, to be converted to thecorresponding compound of the general formula [I].

[0500] Production method 5

[0501] Production method 5 comprises reacting a compound of the generalformula [XIII] with a compound selected from the group consisting ofcarbonyldiimidazole, triphosgene [i.e., bis(trichloromethyd)carbonate],diphosgene [i.e., trichloromethyl chloroformate], methyl chloroformate,ethyl chloroformate, phenyl chloroformate, methyl chlorothioformate,dimethyl carbonate, diethyl carbonate, S,S′-dimethyl dithiocarbonate,S,S′-diethyl dithiocarbonate and urea, preferably in the presence of abase, to form benzimidazolone skeleton. Its scheme is shown by thefollowing formula.

[0502] in the formulae, R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ringhave the earlier defined significations.

[0503] In this reaction, normally 0.95-10 moles, preferably 1.1-2 molesof a compound such as carbonyldiimidazole, triphosgene, diphosgene,methyl chloroformate, ethyl chloroformate, phenyl chloroformate, methylchlorothioformate, dimethyl carbonate, diethyl carbonate, S,S′-dimethyldithiocarbonate, S,S′-diethyl dithiocarbonate or urea is used per moleof a compound of the general formula [XIII].

[0504] This reaction can be performed in the presence of a base wherenecessary, and as the base an organic base such as triethylamine,diisopropylethylamine or 4-(dimethylamino)pyridine; an inorganic basesuch as sodium hydride, sodium carbonate, potassium carbonate or sodiumhydrogencarbonate can be named for example. The use rate of the base is0.9-5 moles, preferably 1.0-4.0 moles, per mole of the compound of thegeneral formula [XIII].

[0505] The reaction is normally carried out in an inert solvent,examples of which include ethers such as ethyl ether, tetrahydrofuran,dioxane and the like; halogenated hydrocarbons such as methylenechloride, chloroform, 1,2-dichloroethane and the like; aromatichydrocarbons such as benzene, toluene, chlorobenzene, xylene and thelike; aprotic polar solvents such as N,N-dimethylformamide,hexamethylphosphoric triamide and the like; or mixed solvents of theforegoing.

[0506] Reaction temperature may be, for example, in the range of 0-150°C., preferably 10-100° C., and the reaction normally terminates in 5minutes -48 hours, preferably in 10 minutes -24 hours.

[0507] After termination of the reaction, excessive reagent is removedby the means known per se, to provide a crude product of benzimidazolonederivative of the general formula [I].

[0508] Where amino, hydroxyl or like groups which do not participate inthe reaction are present, the reaction is preferably carried out afterthey are suitably protected by amino-protective group orhydroxyl-protective group, such protective groups being removed afterthe reaction.

[0509] The compounds represented by the general formula [XIII] can beprepared following the methods which are described, for example, inInternational Publication WO97/16192 or Patent Application No. Hei 11(1999)-291232.

[0510] Of the production methods 1-5, Production methods 1-3 or 5 arepreferred, inter alia, Production method 2.

[0511] In the Production methods 1-5, the reaction liquids after thereactions in occasions contain excessive reagent, side-products or thelike. By isolating and purifying the reaction liquids by the means knownper se after optional condensation step, the benzimidazolone derivativesof the general formula [I] can be recovered.

[0512] The isolation and purification can be accomplished by carryingout such separation means as column chromatography using an adsorptiveresin such as silica gel, alumina or the like, or ion-exchange resin;thin-layer chromatography, high performance liquid chromatography,solvent-extraction or recrystallization/represipitation either singly orin combination.

[0513] Furthermore, where a compound of the general formula [I] is amixture of stereoisomers, optical isomer(s) therein may be isolated bythe means known per se.

[0514] The benzimidazolone derivatives represented by the generalformula [I] can be converted to pharmaceutically acceptable saltsthereof by the means known per se. Conversely, conversion from salts tofree compounds can also be performed by the means known per se.

[0515] As preferred salts of the benzimidazolone derivatives representedby the general formula [I], for example, hydrochloride, hydrobromide,hydroiodide, sulfate, nitrate, phosphate, perchlorate, maleate,fumarate, tartarate, citrate, ascorbate, benzoate, methanesulfonate,isethionate, benzenesulfonate, 4-toluenesulfonate and the like can benamed, among which hydrochloride, hydrobromide, phosphate, tartarate,citrate and methanesulfonate are preferred.

[0516] Pharmacological activities of the benzimidazolone derivativesrepresented bv the general formula [I]

[0517] Utility of the compounds of the present invention has beenverified by the following test on inhibition of binding to muscarinicreceptors.

[0518] Test on inhibition of binding to muscarinic receptors

[0519] The test was performed according to a modification of the methodof Hargreaves, et al. (Br. J. Pharmacol. 107: 494-501, 1992). Namely,muscarinic acetylcholine receptors of human m₁, m₂, m₃, m₄ and m₅expressed in CHO cells (Receptor Biology, Inc.) were incubated with 0.2nM [³H]-N-methylscopolamine (82Ci/mmol, New England Nuclear, Inc.) and atest compound, either in 0.5 ml of 50 mM Tris-HCI, 10 mM MgCl₂, 1 mMEDTA solution (pH 7.4) (human m₁, m3 and m₅ samples) or in 0.5 ml of 50mM tris-HCl, 10 mM MgCl₂, 1 mM EDTA, 5000 nM GTPγS solution (pH 7.4)(human m₂ and m₄ samples) for 120 minutes at room temperature (about20-25° C.), followed by suction filtration over a glass filter(UniFilter plate-GF/C; Packard). Then the filter was washed four timeswith 1 ml of ice-cooled Tris-HCI buffer and dried at 50° C. for an hour.After adding a scintillator (Microscinti 0; Packard), the radioactivityof [³H]-N-methylscopolamine binding to the filter was counted with amicroplate scintillation counter (TopCount; Packard). Non-specificreceptor binding of [³H]-N-methylscopolamine was measured by adding 1 μMN-methylscopolamine. According to the method of Cheng and Prusoff(Biochem. Pharmacol. 22: 3099-3108, 1973), the binding affinity of eachsample compound of the present invention for muscarinic receptors isexpressed by inhibition constant (Ki) which is calculated from theconcentration (IC₅₀) of the sample compound which achieves 50%inhibition of binding of [³H]-N-methylscopolamine, the labeled ligand.Smaller inhibition constant (Ki) represents stronger tendency to bind tomuscarinic receptors, i.e., a higher binding inhibitory effect. TABLE 1Inhibitory Action against Binding to Muscarinic Receptors Selectivity(times) Ki (nM) m₁/ m₂/ m₃/ m₅/ Compound m₁ m₂ m₃ m₄ m₅ m₄ m₄ m₄ m₄Example 4 28 73 7400 4.5 260 6.1 16 1600 57 Example 9 25 31 1700 1.7 45015 19 1000 270 Example 12 22 24 4500 2.3 220 9.7 11 2000 99

[0520] As is clear from the results indicated in above Table 1, thosecompounds of the present invention exhibited selective inhibitory actionagainst binding to muscarinic m₁ and m₄ receptors rather than to m₂, m₃and m₅ receptors. In particular, they exhibited strong activity againstbinding to m₄ receptor.

[0521] Pharmaceutical compositions containing benzimidazolonederivatives of the general formula [I] or salts thereof

[0522] Compounds represented by the structural formula [I] of thepresent invention are useful as drug for treating or preventingParkinson's disease, drug-induced parkinsonism, dystonia, akinesia,pancreatitis, bilestone/cholecystitis, biliary dyskinesia, achalasia,pain, itch, cholinergic urticaria, irritable bowel syndrome, vomiting,nausea, dizziness, Meniere's disease, motion sickness such as spacesickness, sea sickness and car sickness, and urinary disturbance.Pharmaceutical compositions can be formulated using these compounds asthe active ingredient and further adding pharmaceutically acceptableadjuvants.

[0523] As the dosage form of these pharmaceutical compositions, variousforms can be selected, for example, solid preparations such as tablets,capsules, powders, granules and triturates; and liquid preparations suchas solutions suspension syrups and injections. Depending on their forms,the preparations can be used a peroral or parenteral drugs. Thesepreparations may be formulated by known means such as mixing, kneading,granulating, compression molding, punching, coating, sterilizing,emulsifying and the like, according to their dosage forms.

[0524] While those solid preparations can be prepared from the compoundsof the present invention only, into tablets, capsules, granules orpowders, they may be prepared using pharmaceutically acceptable,suitable adjuvants. Examples of such adjuvants include saccharides suchas lactose and glucose; starch such as corn starch, wheat and rice;fatty acid such as steraric acid; inorganic salts such as magnesiumaluminate, magnesium metasilicic aluminate, (heavy) magnesium oxide,(precipitated) calcium carbonate, anhydrous calcium phosphate, lightsilicic anhydride and titanium oxide; synthetic polymers such aspolyvinyl alcohol, polyvinylpyrrolidone and polyalkylene glycol; fattyacid salts such as calcium stearate and magnesium stearate; alcoholssuch as cetyl alcohol, stearyl alcohol and benzyl alcohol; syntheticcellulose derivatives such as methyl cellulose, carboxymethyl cellulose,ethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethylcellulose; crystalline cellulose; carboxylic acid such as citric acidand sodium citrate; glycols such as propylene glycol and polyalkyleneglycol; surfactants such as sorbitan fatty acid ester, polysorbate andsucrose fatty acid ester; and those conventionally used adjuvants suchas water, sorbitol, polyoxyethylene, gelatine, talc, microcrystallinewax, white petrolatum, vegetable oil, hardened custor oil, gum Arabic,cyclodextrin, hydroxypropyl cyclodextrin and the like.

[0525] These solid preparations such as tablets, capsules, granules andpowders generally contain 0.1-100% by weight, preferably 0.1-20% byweight, of the active ingredient.

[0526] In liquid preparations, pharmaceutically acceptable, suitableadjuvants that are customarily used for liquid preparations, such aswater, alcohols, vegetable oils, e.g., soy bean oil, peanut oil andsesame oil, and the like can be used, to prepare such dosage forms assuspension, syrup or injection. Where necessary, non-ionic surfactantmay also be used.

[0527] In particular, as suitable solvent for intramuscular injection,intravenous injection or hypodermic injection used for parenteraladministration, distilled water for injection, aqueous lidocainehydrochloride solution (for intramuscular injection), physiologicalsaline, aqueous glucose solution, ethanol, liquid for intravenousinjection (e.g., aqueous solutions of citric acid, sodium citrate or thelike) or electrolytic solution (for intravenous drip or intravenousinjection), and mixed solutions of the foregoing can be named. Theseinjections can take such forms as, besides solution form, powder formwithout or with suitable adjuvant(s), to be dissolved prior to actualuse. These injections normally contain 0.1-10% by weight, preferably1-5% by weight, of the active ingredient. Also the liquid preparationsfor oral administration such as suspension and syrup contain 0.5-10% byweight of the active ingredient.

[0528] Where the compounds of the present invention are used fortreatment or prophylaxis of, for example, Parkinson's disease,drug-induced parkinsonism, dystonia, akinesia, pancreatitis,bilestone/cholecystitis, biliary dyskinesia, achalasia, pain, itch,cholinergic urticaria, irritable bowel syndrome, vomiting, nausea,dizziness, Meniere's disease, motion sickness such as space sickness,sea sickness and car sickness and urinary disturbance, their dosagelevel and dosage schedule vary according to the sex, age, body weight,severity of symptoms of individual patient, type and range of thedesired therapeutic effect. Generally for oral administration, they arepreferably administered in a daily dose of 0.01 to 10 mg/kg for adultsand this daily dose may be given at a time or in several divided doses.For parenteral administration, they are preferably administered in adaily dose of 0.003 to 3 mg/kg, at a time or in several divided doses.Depending on patient′ s symptoms, these preparations can also beadministered for prophylactic treatment.

OPTIMUM EMBODIMENTS FOR WORKING THE INVENTION

[0529] Hereinafter the present invention is explained more specifically,referring to working examples which however do not incur any limitationson the present invention. In the examples, ¹H-NMR was measured, usingtetramethylsilane as the standard substance.

[0530] Production Example 1

[0531]1-[1-[2-(Piperidin-4-yl)ethyl]pineridin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride

[0532] To a solution of 240 mg of piperidine-4-ethanol in 3 ml ofchloroform, 446 mg of DIBOC (di-tert-butyldicarbonate) was added andstirred for 3 hours at room temperature. The reaction liquid was dilutedwith chloroform, and the chloroform layer was washed successively withsaturated aqueous sodium hydrogencarbonate solution and saturated brine,dried over anhydrous sodium sulfate and concentrated. The residue soobtained was purified on silica gel chromatography(chloroform/methanol=30/1) to provide 456 mg of1-(tert-butoxycarbonyl)piperidine-4-ethanol, which was then dissolved in2 ml of chloroform. To the solution 205 μl of methanesulfonyl chlorideand 1 ml of triethylamine, followed by 10 hours' stirring at roomtemperature. Saturated sodium hydrogencarbonate was added to thereaction liquid, which was then extracted with chloroform three times.This solution was dried on anhydrous sodium sulfate and concentrated. Tothe residue, 20 ml of dimetylformamide, 499 mg of1-(piperldin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one, 477 mg ofpotassium carbonate and 38 mg of potassium iodide were added, followedby 10 hours' stirring at 80° C. After cooling the reaction liquid,chloroform and saturated aqueous sodium hydrogencarbonate solution wereadded thereto, and the resulting mixture was shaken to separate theorganic layer. The organic layer was dried on anhydrous sodium sulfateand removed of the solvent. The resulting residue was purified on silicagel chromatography, to provide 275 mg of1-[1-[2-[1-tert-butoxycarbonylpiperidin-4-yl]ethyl]piperidin-4-yl-]1,3-dihydro-2H-benzimidazol-2-one. To this compound, 10 ml of 10% hydrogenchloride/methanol was added, followed by 6 hours' stirring at roomtemperature. The reaction liquid was concentrated, to which methanol wasadded and distilled under reduced pressure to remove excess of hydrogenchloride and to provide the title compound.

[0533] Example 1

[0534] 1-[1-[2-(1-Benzoylpiperidin-4-yl)ethyl]-piperidin-4-yl]-13-dihydro-2H-benzimidazol-2-one

[0535] To 20 mg of1-[l-[2-(piperidin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride which was synthesized in Production Example 1, 10 mg ofbenzoyl chloride, 27 mg of diisopropylethylamine and 2 ml of chloroformwere added, and sonicated for 30 minutes. Then 20 mg of piperidine wasadded to the system followed by 10 minutes' standing. The resultingreaction mixture was concentrated, and the residue was purified onsilica gel chromatography (chloroform/methanol=15/1) to provide 14 mg ofthe title compound as a colorless oil.

[0536]¹H-NMR(CDCl₃)δ: 1.04-2.08(10H,m),2.08-2.32(2H,m),2.32-2.68(4H,m),2.68-3.22(3H,m),3.60-3.88(1H,m),4.30-4.80(2H,m),7.00-7.60(8H,m),7.80-7.87(1H,m),9.31(1H,brs)ESI-MS(M+H)⁺:433

[0537] Example 2

[0538]1-[1-[2-[1-(4-Chlorophenylsulfonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0539] Conducting the operations according to Example 1 except that thebenzoyl choride was replaced with 4-chlorobenzenesulfonyl chloride, thetitle compound was obtained as a colorless, amorphous substance.

[0540]¹H-NMR(CDCl₃)δ:0.75-2.60(17H,m),2.90-3.15(2H,m),3.65-3.90(2H,m),4.20-4.45(1H,m),6.95-7.15(3H,m),7.15-7.35(1H,m),7.52(2H,d,J=8.4Hz),7.71(2H,d,J=8.4Hz), 8.87(1H,s)ESI-MS(M+H)⁺:503/505

[0541] Example 3

[0542]1-[1-[2-[1-[4-(trifluoromethoxy)phenylsulfonyllpiperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0543] Conducting the operations according to Example 1 except that thebenzoyl choride was replaced with 4-(trifluoromethoxy)-benzenesulfonylchloride, the title compound was obtained as a colorless, amorphoussubstance.

[0544]¹H-NMR(CDCl₃)δ: 1.10-2.60(17H,m),2.95-3.15(2H,m),3.70-3.90(2H,m),4.25-4.45(1H,m),6.90-7.15(3H,m),7.15-7.30(1H,m),7.36(2H,d,J=9.0Hz),7.83(2H,d,J=9.OHz), 9.47(1H,s)ESI-MS(M+H)⁺:553

[0545] Example 4

[0546]1-[1-[2-[1-(Pyrazinylcarbonyl)piperidin-4-yl]ethyl])piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0547] To 73 mg of1-[1-[2-(piperidin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride which was synthesized in Production Example 1, 28 mg ofpyrazinecarboxylic acid, 101 ,μl of triethylamine and 14 mg of1-hydroxybenzotriazole were added, and the mixture was suspended in 5 mlof chloroform. Then 52 mg of1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride was addedto the suspension, and the resulting reaction mixture was stirred for 3hours at room temperature. To the reaction liquid, ethyl acetate andsaturated aqueous sodium hydrogencarbonate solution were added and mixedby shaking, to recover the separated organic layer. The organic layerwas successively washed with saturated aqueous sodium hydrogencarbonatesolution and saturated brine, dried over anhydrous sodium sulfate, andthe solvent was distilled off. The resulting residue was purified onsilica gel chromatography (chloroform/methanol=10/1) to provide 40 mg ofthe title compound as a colorless oil.

[0548]¹H-NMR(CDCl₃)δ: 1.20-1.98(10H,m),2.05-2.20(2H,m),2.30-2.60(3H,m),2.75-2.95(1H,m),3.00-3.20(3H,m),3.80-3.98(1H,m),4.25-4.50(1H,m),4.65-4.85(1H,m),6.95-7.17(3H,m),7.20-7.40(1H,m),8.56(1H,dd,J=1.5Hz,2.7Hz),8.63(1H,d,J=2.7Hz),8.90(1H,d,J=1.5Hz),9.57(1H,brs) ESI-MS(M+H)⁺:435

[0549] Production Example 2

[0550]1-[1-[2-(1,2,5.6-Tetrahydro-4-pyridyl)ethyl]niperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride

[0551] A solution of 300 mg of(1-tert-butoxycarbonylpiperidin-4-ylidene)acetic acid ethyl ester (whichhad been prepared by Horner-Wittig reaction of commercially available1-tert-butoxycarbonyl-4-piperidone and triethyl phosphonoacetate by themethod known per se) in 30 ml of tetrahydrofuran was cooled to −78° C.,to which 1.3 ml of a tetrahydrofuran solution (1.5 M) of lithiumdiisopropylamide was added and stirred for 15 minutes. Thereafter 150 μlof acetic acid was added, and the system was warmed up to roomtemperature, over an hour. The reaction liquid, to which saturatedaqueous sodium hydrogencarbonate solution was added, was extracted withchloroform. The chloroform layer was dried over sodium sulfate and thesolvent was distilled off therefrom to provide 329 mg of(1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)acetic acid ethylester. This ester was dissolved in 10 ml of tetrahydrofuran, cooled to0° C., and to which 80 mg of lithium aluminium hydride was added. Thereaction liquid was stirred for 15 minutes and to which an excessiveamount of sodium sulfate decahydrate was added, followed by 2 hours'stirring at room temperature. The insoluble matter was filtered off, andthe filtrate was concentrated to provide 228mg of2-(1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridin-4-yl)ethanol.

[0552] Of the above product, 25 mg was dissolved in 3 ml of ethylacetate, to which 16 mg of methanesulfonyl chloride and 35 mg oftriethylamine were added, followed by 30 minutes' stirring at roomtemperature. The reaction liquid, to which saturated aqueous sodiumhydrogencarbonate solution was then added, was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, driedover anhydrous magnesium sulfate and removed of the solvent bydistillation. The resulting residue was dissolved in 3 ml ofacetonitrile, and to the acetonitrile solution 30 mg of1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one, 35 mg of potassiumcarbonate and 5 mg of potassium iodide were added, followed by heatingto 70° C. and 7 hours' stirring. The reaction liquid was cooled andwater was added thereto, followed by extraction with ethyl acetate. Theethyl acetate layer was successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate and the solvent was distilledoff. The resulting residue was purified on silica gel chromatography(chloroform/methanol=10/1) to provide 35.8 mg of the title compound as acolorless oil.

[0553] Example 5

[0554]1-[1-[2-[1,2,5,6-Tetrahydro-1-(pyrazinylcarbonyl)-4-pyridyl]ethyl]-piperidin-4-yl]-13-dihydro-2H-benzimidazol-2-one

[0555] Conducting the operations similarly to those in Example 4 exceptthat

[0556]1-[1-[2-(1,2,5,6-tetrahydro-4-pyridyl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride which was synthesized by the method of ProductionExample 2 was used in place of1-[1-[2-(piperidin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride, the title compound was obtained.

[0557]¹H-NMR(CDCl₃)δ:0.80-2.70(12H,m),3.02-3.26(2H,m),3,59-4.50(5H,m),5.32-5.60(1H,m),7.00-7.33(4H,m),8.13-8.22(1H,m),8.50-8.60(1H,m),8.60-8.69(1H,m), 8.92-8.99(1H,m)ESI-MS(M+H)⁺:433

[0558] Production Example 3

[0559]1-[1-[2-(3-Methylene-4-pii)eridy)ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride

[0560] In 30 ml of xylene, 1.10 g of1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-methanol (which hadbeen prepared by the method described in Tetrahedron, Vol.54, No.25,p.7045, 1998), 914 mg of ethyl orthoformate and 130 mg of2,4-dinitrophenol were dissolved, and the formed solution was heated to140° C. and stirred for 7 hours while removing the ethanol as formed.The reaction liquid was cooled, then ethyl acetate was added thereto andthe organic layer was successively washed with 1N hydrochloric acid,saturated aqueous sodium hydrogencarbonate solution and saturated brine,dried over anhydrous sodium sulfate and removed of the solvent bydistillation. The resulting residue was purified on silica gel columnchromatography (hexane/ethyl acetate=10/1) to provide 692 mg of1-tert-butoxycarbonyl-3-methylenepiperidine-4-acetic acid ethyl ester.The product was dissolved in 20 ml of tetrahydrofuran, cooled to 0° C.,111 mg of lithium aluminium hydride was added thereto, and stirred foran hour. Then an excessive amount of sodium sulfate decahydrate wasadded to the reaction liquid and stirred for 15 minutes. The resultingmixture was filtered, and the filtrate was concentrated to provide 558mg of crude 1-tert-butoxycarbonyl-3-methylenepiperidine-4-ethanol.

[0561] Of the above product, 100 mg was dissolved in 3 ml of chloroform,and to the solution 35 μl of methanesulfonyl chloride and 173 μl oftriethylamine were added, followed by 2 hours' stirring at roomtemperature. The reaction liquid was partitioned between chloroform andsaturated aqueous sodium hydrogencarbonate solution, and the organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and the solvent was distilled off. The residue was dissolved in2 ml of dimethylformamide and to the solution 99 mg of1,3-dihydro-1-(4-piperidyl)-2H-benzimidazol-2-one and 86 mg of potassiumcarbonate were added, followed by heating to 80° C. and 5 hours'stirring. The reaction liquid was cooled and partitioned between ethylacetate and saturated aqueous sodium hydrogencarbonate solution. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate and the solvent was distilled off. The resulting residuewas purified on silica gel chromatography (chloroform/methanol=10/1) toprovide 32 mg of1-[1-[2-(1-tert-butoxycarbonyl-3-methylene-4-piperidyl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,of which 30 mg was dissolved in 2 ml of 10% hydrogen chloride/methanoland stirred for 8 hours at room temperature. The reaction liquid wasconcentrated, to which further methanol was added and from which theexcess of hydrogen chloride was distilled off under reduced pressure toprovide 29 mg of the title compound as a colorless solid.

[0562] Example 6

[0563]1-[1-[2-[1-(Pyrazinylcarbonyl)-3-methylene-4-piperidyl]ethyl]-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one

[0564] Conducting the operations similarly to those in Example 4 exceptthat[1-[2-(piperidin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride was replaced with1-[1-[2-(3-methylene-4-piperidyl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride which was synthesized in Production Example 3, the titlecompound was obtained.

[0565]¹H-NMR(CDCl₃)δ: 1.20-2.65(13H,m),3.00-3.20(2H,m),3.40-3.70(1H,m),3.70-4.65(3H,m),4.30-4.45(1H,m),4.70-5.18(2H,m),6.99-7.15(3H,m),7.20-7.35(1H,m),8.50-8.70(2H,m),8.92(1H,s),9.10-9.35(1H,brs) ESI-MS(M+H)⁺:447

[0566] Production Example 4

[0567](S*)-1-[1-[2-(perhydroazepin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride and(R*)-1-[1-[2-(perhydroazepin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride (S* and R* are provisional configurations allotted todistinguish the stereoisomers, standing for the configuration at4-position of perhydroazepine)

[0568] Into a suspension of 50 mg of sodium hydride in 5 ml oftetrahydrofuran, which was cooled to 0° C., 210 μl of ethyldiethylphosphonoacetate was added. After its temperature was restored toroom temperature, the system was stirred for an hour. Cooling thereaction liquid to 0° C. once again, a tetrahydrofuran (5 ml) solutioncontaining 205 mg of 1-tert-butoxy-carbonylperhydroazepin-4-one (thiscompound is described in International Publication WO 00/00203) wasadded, followed by 40 minutes' stirring at room temperature. Saturatedaqueous ammonium chloride solution was added to the reaction liquid, thetetrahydrofuran was distilled off, further water was added, and thesystem was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and from which thesolvent was distilled off. The residue was purified on silica gelchromatography (eluted first with hexane/ethyl acetate=10/1, andthen=7/1) to provide 173 mg of(1-tert-butoxycarbonylperhydroazepin-4-ylidene)acetic acid ethyl esteras a colorless oil.

[0569] Thus obtained compound was dissolved in a liquid mixture of 5 mlof methanol and 1 ml of tetrahydrofuran. To the solution 39 mg of 10%palladium-on-carbon was added, and stirred for 2 hours at roomtemperature and in hydrogen exerting 1 atmospheric pressure. Thereaction liquid was filtered, the filtrate was concentrated, and theresulting residue was dissolved in 6 ml of diethyl ether. The ethersolution was cooled to 0° C., and to which 23 mg of lithium aluminiumhydride was added, followed by 3 hours' stirring in nitrogen atmosphere.Then an excessive amount of sodium sulfate decahydrate was added to theether solution, its temperature was restored to room temperature, andthe solution was stirred for 90 minutes. The insoluble matter wasdistilled off and the filtrate was concentrated to provide 150 mg of2-(1-tert-butoxycarbonylperhydro-azepin-4-yl)ethanol as a colorless oil.The oil was dissolved in 10 ml of ethyl acetate, and to the solution 170μl of triethylamine and 52 μl of methanesulfonyl chloride were added,followed by 15 minutes' stirring at room temperature. Saturated aqueoussodium hydrogencarbonate solution was added to the reaction liquid andextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate and removed of the solvent bydistillation.

[0570] Thus obtained residue was dissolved in 6 ml of dimethylformamide,to which 132 mg of 1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,168 mg of potassium carbonate and 10 mg of potassium iodide were added,followed by heating to 80° C. and 16 hours' stirring. The reactionliquid was restored to room temperature, diluted with ethyl acetate, andthe ethyl acetate layer was washed three times with water and once withsaturated brine, dried over magnesium sulfate, and the solvent wasdistilled off. The resulting residue was purified on silica gelchromatography (chloroform / methanol=10/1), to provide 153 mg of1-[1-[2-(1-tert-butoxycarbonylperhydroazepin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-oneas a colorless oil. The oil was optically resolved using an opticallyactive column [Chiral Cell OD (Daicel Chemicals) hexane/isopropylalcohol/diethylamine=90/10/0.1], to provide 27 mg of earlier elutedisomer, 39 mg of later eluted isomer and 33 mg of their mixture. Fordistinguishing the two isomers, the earlier eluted isomer wasexpediently referred to as (R*)-1-[-[2-(1-tert-butoxycarbonylperhydroazepin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-oneand the later eluted, as(S*)-1-[1-[2-(1-tert-butoxycarbonylperhydroazepin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.The two isomers were led to the title compounds, respectively, bytreating them with each 1 ml of 10% hydrogen chloride/methanol.

[0571] Example 7

[0572](S*)-1-[1-[2-[1-(Pyrazinylcarbonyl)perhydroazepin-4-yl]ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one(S* is a provisional configuration allotted to distinguish thestereoisomer, showing the configuration at 4-position of theperhydroazepine.)

[0573] Conducting the operations same to those in Example 4 except that1-[1-[2-(piperidin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride was replaced with (S*)1-[1-[2-(perhydroazepin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride, which was produced in Production Example 4, the titlecompound was obtained.

[0574]¹H-NMR(CDCl₃)δ: 1.21-2.21(12H,m),2.35-2.55(4H,m),3.05-3.15(2H,m),3.34-3.74(4H,m),3.80-4.00(1H,m),4.26-4.50(1H,m),7.00-7.10(3H,m),7.29-7.38(1H,m),8.50-8.95(3H,m),9.73(1H,brs) ESI-MS(M+H)⁺:449

[0575] Example 8

[0576](R*)-1-[1-[2-[1-(pyrazinylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one(R* is a provisional configuration, showing the configuration at4-position of the perhydroazepine)

[0577] Conducting the operations same to those in Example 7 except that(S*)-1-[1-[2-(perhydroazapin-4-yl)ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onewas replaced with(R*)-1-[1-[2-(perhydroazapin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride, which was produced inProduction Example 4, the title compound was obtained.

[0578]¹H-NMR(CDCl₃)δ: 1.21-2.21(12H,m),2.35-2.55(4H,m),3.05-3.15(2H,m),3.34-3.74(4H,m),3.80-4.00(1H,m),4.26-4.50(1H,m),7.00-7.10(3H,m),7.29-7.38(1H,m),7.94(1H,brs),8.50-8.95(3H,m) ESI-MS(M+H)⁺:449

[0579] Example 9

[0580](S*)-1-[1-[2-[1-(3-pyridylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one(S* is a provisional configuration allotted to distinguish thestereoisomers, showing the configuration at 4-position of theperhydroazepine)

[0581] Conducting the operations same to those in Example 7 except thatnicotinic acid was used in place of pyrazinecarboxylic acid, the titlecompound was obtained.

[0582]¹H-NMR(CDCl₃)δ:1.21-2.21(13H,m),2.30-2.60(4H,m),3.00-3.15(2H,m),3.25-3.65(3H,m),3.81-4.02(1H,m),4.25-4.45(1H,m),7.00-7.10(3H,m),7.20-7.39(2H,m),7.74(1H,d,J=7.7Hz),8.27(1H,brs),8.60-8.70(2H,m) ESI-MS(M+H)⁺:448

[0583] Example 10

[0584] (R*)1-[1-[2-[1-(3-pyridylcarbonyl)perhydroazenin-4*-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one(R* is a provisional configuration, indicating an isomer in respect ofthe 4* substituent.)

[0585] Operations same to those in Example 8 were performed except thatnicotinic acid was used in place of pyrazinecarboxylic acid, to obtainthe title compound.

[0586]¹H-NMR(CDCl₃)δ: 1.21-2.21(13H,m),2.30-2.60(4H,m),3.00-3.15(2H,m),3.25-3.65(3H,m),3.81-4.02(1H,m),4.25-4.45(1H,m),7.01-7.11(3H,m),7.20-7.39(2H,m),7.74(1H,d,J=7.7Hz),8.60-8.70(2H,m),9.13(1H,brs) ESI-MS(M+H)⁺:448

[0587] Production Example 5

[0588] 1-[1-[2-(Piperidin-4-yl)propyl]pi~ieridin-4-yl]-13-dihydro-2H-benzimidazol-2-one

[0589] To a solution of 765 mg of2-(1-tert-butoxycarbonylpiperidin-4-ylidene)propionic acid ethyl ester(prepared following the method of synthesis as described inInternational Publication WO 99/40070) in 4 ml of methanol, 100 mg of10% palladium-on-carbon was added, and stirred for 4 hours at roomtemperature, in hydrogen atmosphere. Then the reaction liquid wasfiltered and the filtrate was concentrated to provide 743 mg of2-(1-tert-butoxycarbonylpiperidin-4-yl)propionic acid ethyl ester as aslightly yellowish oil. Of said product, 306 mg was dissolved in 9 ml oftetrahydrofuran and cooled to 0° C. To said tetrahydrofuran solution 150mg of lithium aluminium hydride was added portionwise. The reactionliquid was stirred at 0° C. for an hour, sodium sulfate decahydrate wasadded thereto and the temperature was restored to room temperature,followed by an overnight's stirring. The reaction liquid was filtered,and the filtrate was concentrated to provide 313 mg of2-(1-tert-butoxycarbonylpiperidin-4-yl)propanol as a yellowish oil. Ofsaid oil, 210 mg was dissolved in 2 ml of dichloromethane and thesolution was added to another −78° C. solution of 188 μl of oxarylchloride and 359 μl of dimethylsulfoxide in dichloromethane (4 ml) overa period of 5 minutes. After 30 minutes' stirring, a solution of 993 plof triethylamine in 0.5 ml of dichloromethane was added to the reactionliquid and the temperature of the system was restored to roomtemperature, followed by 25 minutes' stirring. After addition of water,the reaction liquid was extracted with ethyl acetate and the ethylacetate layer was washed twice with water, dried over anhydrous sodiumsulfate and concentrated to provide 163 mg of a pale yellow oil.

[0590] To said compound 147 mg of1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one and 2.7 ml of amethanolic solution of sodium cyanoborohydride and zinc chloride (each0.3 mole/liter) were added, followed by 20 hours' stirring at roomtemperature. To the resulting reaction liquid saturated aqueous sodiumhydrogencarbonate solution and saturated brine were added, and extractedwith ethyl acetate. The ethyl acetate layer was successively washed withsaturated aqueous sodium hydrogencarbonate solution and saturated brine,dried over anhydrous sodium sulfate and the solvent was distilled off.The residue was purified on silica gel chromatography (ethylacetate/hexane=1/1, 1/2) to provide 97 mg of1-[1-[2-(1-tert-butoxycarbonyl-piperidin-4-yl)propyllpiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-oneas a colorless, amorphous substance.

[0591] Of the product, 65 mg was dissolved in 1 ml of 10% hydrogenchloride/methanol, and the formed methanol solution was stirred for 2hours at room temperature. The reaction liquid was concentrated, towhich 1N aqueous sodium hydroxide solution was added until pH reached10, and the solution was extracted with chloroform three times.Chloroform layers were combined, dried over anhydrous sodium sulfate,and the solvent was distilled off to provide 50 mg of the title compoundas a colorless, amorphous substance.

[0592] Example 11

[0593]1-[1-[2-[1-(Pyrazinylcarbonyl)piperidin-4-yl]propyl])piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0594] To 6.4 mg of1-[1-[2-(piperidin-4-yl)propyllpiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onewhich was synthesized by the method of Production Example 5, 3.6 mg ofpyrazinecarboxylic acid, 5.5 mg ofN-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide, 4.4 mg of1-hydroxybenzotriazole, 10 μl of triethylamine and 1 ml of chloroformwere added, followed by 3 hours' stirring at room temperature. To thereaction liquid, 1N aqueous sodium hydroxide solution was added untilthe latter' s pH reached 10, followed by extraction with chloroform. Thechloroform solution was washed with saturated brine, dried overanhydrous sodium sulfate and concentrated. Thus obtained residue waspurified on silica gel chromatography (chloroform/methanol=10/1) toprovide 6.0 mg of the title compound as a colorless solid.

[0595]¹H-NMR(CDCl₃)δ: 0.92(3H,d,J=4.8Hz), 1.23-1.88(8H,m),2.00-2.20(3H,m),2.26-2.56(3H,m),2.72-2.88(1H,m),2.92-3.18(3H,m),3.90-4.00(1H,m),4.28-4.40(1H,m), 4.78-4.88(1H,m),7.00-7.16(3H,m),7.20-7.31(1H,m),8.52-8.59(1H,m),8.60-8.66(1H,m),8.91(1H,s), 8.95-9.12(1H,m)ESI-MS(M+H)⁺:449

[0596] Example 12

[0597]1-[1-[2-[1-(3-Pyridylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0598] Operations same as in Example 11 were conducted except thatnicotinic acid was used in place of pyrazinecarboxylic acid, to providethe title compound as a colorless solid.

[0599]¹H-NMR(CDCl₃)δ: 0.93(3H,d,J=6.3Hz), 1.20-1.95(8H,m),2.02-2.20(3H,m),2.29-2.56(3H,m),2.70-2.92(1H,m),2.95-3.16(3H,m),3.70-3.85(1H,m),4.28-4.40(1H,m),4.70-4.88(1H,m),7.01-7.13(3H,m),7.20-7.30(1H,m),7.33-7.41(1H,m),7.76-7.82(1H,m),8.62-8.70(2H,m), 8.93-9.06(1H,m)ESI-MS(M+H)⁺:448

[0600] Example 13

[0601]1-[1-[2-[1-(3-Chlorobenzoyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0602] Operations same as in Example 11 were conducted except that3-chlorobenzoic acid was used in place of pyrazinecarboxylic acid, toprovide the title compound as a colorless, amorphous substance.

[0603]¹H-NMR(CDCl₃)δ: 0.92(3H,d,J=6.6Hz), 1.18-1.90(8H,m),2.00-2.22(3H,m),2.28-2.55(3H,m),2.66-2.75(1H,m),2.93-3.10(3H,m),3.69-3.72(1H,m),4.28-4.40(1H,m),4.70-4.83(1H,m),7.00-7.15(3H,m),7.20-7.57(5H,m), 8.98-9.08(1H,m)ESI-MS(M+H)⁺:481

[0604] Production Example 6

[0605]1-[1-[2-(Piperidin-4-yl)-1-methylethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0606] To a solution of 1.01 g of1-tert-butoxycarbonylpiperidin-4-acetic acid ethyl ester in 4 ml ofmethanol, 2 ml of 4N aqueous sodium hydroxide solution was added andstirred for 3 hours. Then iN hydrochloric acid was added to make thereaction liquid acidic, which reaction liquid was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfateand the solvent was distilled off to provide 840 mg of crude1-tert-butoxycarbonylpiperidine-4-acetic acid. To this crude product, 5ml of chloroform, 318 mg of N,O-dimethylhydroxylamine hydrochloride, 500mg of 1-hydroxybenzotriazole, 623 mg of1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride and 1.13ml of triethylamine were successively added, followed by an overnight' sstirring. Saturated aqueous sodium hydrogencarbonate solution was added,and the reaction liquid was extracted with chloroform. The chloroformlayer was successively washed with water and saturated aqueous ammoniumchloride solution, dried over anhydrous sodium sulfate, and the solventwas distilled off, to provide 796 mg ofN-methyl-N-methoxy-(1-tert-butoxycarbonylpiperidine-4-acetamide). Of theproduct, 353 mg was dissolved in 5 ml of tetrahydrofuran, and 0.62 ml of3M methyl magnesium bromide/ether solution was added thereto at −78° C.,followed by 10 minutes' stirring and further by 40 minutes' stirring at0° C. Additional 0.20 ml of 3M methyl magnesium bromide/ether solutionwas added and stirring was continued for another hour. To the reactionliquid saturated aqueous ammonium chloride solution was added, andextracted with ethyl acetate. The extract was successively washed withwater and saturated brine, dried over anhydrous sodium sulfate and thesolvent was distilled off, to provide 300 mg of crude1-tert-butoxycarbonyl-4-(2-oxopropyl)-piperidine. To 142 mg of thisproduct, 2.5 ml of 1,2-dichloroethane, 128 mg of1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one, 174 mg of sodiumtriacetoxyborohydride and 0.04 ml of acetic acid were added and stirredfor an overnight. Then 0.04 ml of acetic acid, 5 ml of1,2-dichloroethane and 174 mg of sodium triacetoxyborohydride werefurther added to the system, and the mixture was stirred for 5 days. ThepH of the reaction liquid was adjusted to 8 by addition of aqueoussodium hydrogencarbonate solution and aqueous sodium hydroxide solution,ethyl acetate was added and the reaction liquid was separated. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate and the solvent was distilled off. The residue waspurified on silica gel column chromatography (hexane/ethyl acetate=3:1,1:2; chloroform/methanol=100:1, 40:1) to provide 31 mg of1-[1-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-1-methylethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.Twenty-eight (28) mg of said product was dissolved in 2 ml of 10%hydrogen chloride/methanol, stirred for 4 hours at room temperature andthe solvent was distilled off. The pH of the residue was adjusted to 10by addition of iN aqueous sodium hydroxide solution, and the residue wasextracted with chloroform. The extract was dried over anhydrous sodiumsulfate and the solvent was distilled off to provide 21 mg of the titlecompound as a colorless solid.

[0607] Example 14

[0608]1-[1-[2-[1-(3-Pyridylcarbonyl)piperidin-4-yl]-1-methylethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0609] To 9.7 mg of1-[1-[2-(piperidin-4-yl)-1-methylethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onewhich was synthesized by the method of Production Example 6, 1 ml ofchloroform, 4.4 mg of nicotinic acid, 8 mg of1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 6.4 mgof 1-hydroxybenzotriazole and 0.01 ml of triethylamine were added andstirred for an overnight. To the reaction liquid iN aqueous sodiumhydroxide solution and chloroform were added to separate the reactionliquid. The organic layer was dried over anhydrous sodium sulfate, thesolvent was distilled off, and the residue was purified on silica gelchromatography (chloroform / methanol=11: 1) to provide 10.1 mg of thetitle compound as a colorless solid.

[0610]¹H-NMR(CDCl₃)δ:0.98(3H,d,J=6.3Hz), 1. 10-2.00(9H,m),2.27-2.62(4H,m),2.70-2.98(4H,m),3.00-3.18(1H,m),3.65-3.83(1H,m),4.23-4.38(1H,m),4.60-4.82(1H,m),6.98-7.12(3H,m),7.18-7.30(1H,m),7.32-7.45(1H,m),7.70-7.80(1H,m),8.60-8.75(2H,m),9.07-9.18(1H,m) ESI-MS(M+H)⁺:448

[0611] Production Example 7

[0612] 1-(1-[2-[1-(3-Pyridylcarbonyl)piperidin-4-ylidene]ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0613] Ninety (90) mg of2-(1-tert-butoxycarbonylpiperidin-4-ylidine)ethanol was dissolved in 4ml of ethyl acetate, and to which 70 μl of triethylamine and 33 gl ofmethanesulfonyl chloride were added, followed by 15 minutes' stirring atroom temperature. The reaction liquid was diluted with ethyl acetate,washed successively with water and saturated brine, dried over anhydroussodium sulfate and the solvent was distilled off. The residue wasdissolved in 3 ml of dimethylformamide, to which 90 mg of1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one and 150 mg ofpotassium carbonate were added, stirred for 3 hours at room temperature,heated to 80° C., and further stirred for 3 hours. The reaction liquidwas cooled, water was added thereto and the liquid was extracted withethyl acetate. The extract was dried over anhydrous sodium sulfate, andthe solvent was distilled off. The residue was purified on silica gelchromatography (chloroform/methanol=10:1), to provide 15.3 mg of1-[1-[2-[1-(tert-butoxycarbonyl)piperidin-4-ylidene]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,which was dissolved in 2 ml of 10% hydrogen chloride/methanol andstirred for 5 hours at room temperature. The reaction liquid wasconcentrated, and to the residue 2 ml of dimethylformamide, 50 mg of1-hydroxybenzotriazole, 20 gl of triethylamine and 15 mg of1-ethyl-3-[3-(dimethylamino)-propyl/carbondiimide hydrochloride wereadded, followed by an overnight' s stirring at room temperature. Waterand chloroform were added to the reaction liquid to separate the latter.The organic layer was washed with saturated aqueous sodiumhydrogencarbonate solution and saturated brine, dried over anhydroussodium sulfate and the solvent was distilled off. Purifying the residueon silica gel chromatography (chloroform/methanol=10:1), 2.7 mg of thetitle compound was obtained as a colorless oil.

[0614] Example 15

[0615]1-[1-[2-Hydroxy-2-[4-hydroxy-1-(3-pyridylcarbonyl)-piperidin-4-yl]-ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0616] To1-[1-[2-[1-(3-pyridylcarbonyl)piperidin-4-ylidenelethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onewhich was obtained in Production Example 7, 0.1 ml of 2% aqueous osmiumtetroxide solution, 10 mg of N-methylmorpholine-N-oxide, 2 ml ofacetonitrile and 1 ml of water were added at 0° C. and stirred for 15minutes. The temperature was restored to room temperature and the systemwas further stirred for a day. To the reaction liquid ethyl acetate andaqueous sodium sulfite solution were added to separate the liquid, andthe organic layer was dried over anhydrous sodium sulfate, removed ofthe solvent by distillation and purified on silica gel chromatography(chloroform/methanol=10:1) to provide 1.8 mg of the title compound as acolorless oil.

[0617]¹H-NMR(CDCl₃)δ: 0.81-2.80(12H,m),3.00-3.77(6H,m),4.20-4.75(2H,m),7.00-7.57(5H,m),7.72-7.80(1H,m),8.05-8.16(1H,m),8.62-8.70(2H,m) ESI-MS(M+H)⁺:448

[0618] Example 16

[0619]1-[1-[2-[1-(2-Chlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0620] Example 4 was repeated except that 2-chlorobenzoic acid was usedin place of pyrazinecarboxylic acid, to provide the title compound as acolorless oil.

[0621] [M+H]⁺=467

[0622] Example 17

[0623]1-[1-[2-[1-(3-Chlorobenzoyl)piperidin-4-yl]ethyl]-pii)eridin-4-yl]-1,3-dihydro-2H-bezimidazol-2-one

[0624] Example 4 was repeated except that 3-chlorobenzoic acid was usedin place of pyrazinecarboxylic acid, to provide the title compound as acolorless, amorphous substance.

[0625]¹H-NMR(CDCl₃)δ: 1.10-2.00(9H,m),2.05-2.20(2H,m),2.35-2.60(4H,m),2.70-3.15(4H,m),3.60-3.80(1H,m),4.25-4.45(1H,m),4.60-4.75(1H,m),7.00-7.12(3H,m),7.26-7.41(5H,m),9.36(1H,brs) [M+H]+=467

[0626] Example 18

[0627]1-[1-[2-[1-(3-Bromobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0628] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with 3-bromobenzoic acid, to provide the title compound as acolorless, amorphous substance.

[0629] [M+H]+=511,513

[0630] Example 19

[0631]1-[1-[2-[1-(3-Iodobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0632] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with 3-iodobenzoic acid, to provide the title compound as apale yellow, amorphous substance.

[0633] [M+H]⁺=559

[0634] Example 20

[0635]1-[1-[2-[1-(3,5-Dichlorobenzoyl)piperidin-4-yl]ethyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0636] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with 3,5-dichlorobenzoic acid, to provide the title compound asa colorless, amorphous substance.

[0637] [M+H]⁺=501, 503

[0638] Example 21

[0639] 1-[1-[2-[1-(3,4-Dichlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0640] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with 3,4-dichlorobenzoic acid, to provide the title compound asa colorless solid.

[0641] [M+H]⁺=501, 503

[0642] Example 22

[0643]1-[1-[2-[1-(3-Pyridylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0644] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with nicotinic acid, to provide the title compound as acolorless solid.

[0645]¹H-NMR(CDCl₃)δ: 1.10-2.00(9H,m),2.05-2.20(2H,m),2.35-2.55(4H,m),2.70-3.15(4H,m),3.60-3.80(1H,m),4.25-4.45(1H,m),4.60-4.78(1H,m),7.00-7.10(3H,m),7.25-7.40(2H,m),7.68-7.80(1H,m),8.55-8.70(3H,m)

[0646] [M+H]⁺=434

[0647] Example 23

[0648]1-[1-[2-[1-[(4,5-Dichloro-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0649] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with 4,5-dichloronicotinic acid, to provide the title compoundas a colorless solid.

[0650]¹H-NMR(CDCl₃)δ: 1.05-2.60(15H,m),2.70-2.95(1H,m),3.00-3.25(3H,m),3,55-3.80(1H,m),4.25-4.45(1H,m),4.55-4.80(1H,m),6.95-7.15(3H,m),7.15-7.35(1H,m),7.86(1H,d,J=2.1Hz),8.34(1H,s),9.60(1H,s)

[0651] [M+H]⁺=502,504

[0652] Example 24

[0653]1-[1-[2-[1-[(5-Bromo-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0654] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with 5-bromonicotinic acid, to provide the title compound as apale yellow, amorphous substance.

[0655] [M+H]⁺=512, 514

[0656] Example 25

[0657]1-[1-[2-[1-(2-Thenoyl)piperidin-4-yl]ethyl]-pipendin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0658] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with thiophene-2-carboxylic acid, to provide the title compoundas a pale yellow, amorphous substance.

[0659] [M+H]⁺=439

[0660] Example 26

[0661]1-[1-[2-[1-[(2-Propylthio-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0662] Example 4 was repeated except that pyrazinecarboxylic acid wasreplaced with 2-(propylthio)nicotinic acid, to provide the titlecompound as a colorless solid.

[0663]¹H-NMR(CDCl₃)δ:1.03(3H,t,J=7.5Hz),0.80-2.60(18H,m),2.70-2.90(1H,m),2.90-3.30(4H,m),3.30-3,50(1H,m),4.25-4.50(1H,m),4.65-4.85(1H,m),6.90-7.50(6H,m),8.43(1H,d,J=4.8Hz),9.02(1H,s)

[0664] [M+H]⁺=508

[0665] Production Example 8

[0666]1-[1-[(1α,5α,7β)-3-Azabicyclo[3.3.0]octan-7-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0667] With 215 mg of (1α,5α)-3-(tert-butoxycarbonyl)-3-azabicyclo-[3.3.0]octan-7-one, 200 mg of1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one and 15 ml of 0.3 Mmethanolic zinc cyanoborohydride were mixed and stirred for anovernight. Saturated aqueous sodium hydrogencarbonate solution was addedto the reaction liquid, followed by extraction with chloroform. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, removed of the solvent by distillation, and purified on silicagel chromatography (chloroform/methanol=19:1) to provide 240 mg of1-[1-[(1α, 5α,7β)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.This product was dissolved in 10 ml of chloroform and 3 ml oftrifluoroacetic acid was added to the resulting solution, followed by anhour' s stirring at room temperature. The solvent was distilled off, andto the residue saturated aqueous sodium hydrogencarbonate solution wasadded and extracted with chloroform. The chloroform layer was dried overanhydrous magnesium sulfate. Distilling the solvent off, 110 mg of thetitle compound was obtained as a colorless, amorphous substance.

[0668] Example 27

[0669] 1-[1-[(1α, 5α, 7β)-3-(Pyrazinylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0670] To 26 mg of1-[1-[(1α,5α,7β)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onewhich was obtained in Production Example 8, 1 ml of chloroform, 10 mg ofpyrazinecarboxylic acid, 30 g of triethylamine, 16 mg of1-hydroxybenzotriazole and 23 mg of1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride wereadded, and stirred for an overnight at room temperature. Saturatedaqueous sodium hydrogencarbonate solution was added to the reactionliquid, followed by distribution. The organic layer was dried overanhydrous sodium sulfate and the solvent was distilled off. Theresulting residue was purified on silica gel chromatography(chloroform/methanol=10: 1), to provide 11 mg of the title compound as acolorless, amorphous substance.

[0671]¹H-NMR(CDCl₃)δ: 1.35-1.60(2H,m), 1.68-1.95(4H,m),2.06-2.35(4H,m),2.35-2.60(1H,m),2.60-2.82(3H,m), 3.05-3.25(2H,m),3.70-4.00(3H,m),4.27-4.47(1H,m),6.95-7.14(3H,m),7.22-7.38(1H,m),8.55(1H,dd,J=1.4,2.5Hz),8.64(1H,d,J=2.5Hz),9.12(1H,d,J=1.4Hz),9.32(1H,s) [M+H]⁺=433

[0672] Production Example 9

[0673] 1-[l-[(1α, 5α,7α)-3-Azabicyclo[3.3.0]octan-7-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride

[0674] In 20 ml of methanol, 710 mg of (1α,5α)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-one wasdissolved, and 120 mg of sodium borohydride was added to the formedsolution under cooling with ice, followed by an hour′ s stirring.Saturated aqueous ammonium chloride solution and successively ethylacetate were added to the reaction liquid which then was separated. Theorganic layer was dried over anhydrous magnesium sulfate, the solventwas distilled off, and the residue was purified on silica gelchromatography (hexane/ ethyl acetate=1:1,3:7) to provide 540 mg of (1α,5α, 7β)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-ol. Of theproduct, 517 mg was dissolved in 20 ml of chloroform, and 1.6 ml oftriethylamine and 0.26 ml of methanesulfonyl chloride were added to thesolution, followed by 40 minutes' stirring at room temperature.Saturated aqueous sodium hydrogencarbonate solution was added to thereaction liquid which then was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and the solvent was distilled off. The residue was purified on silicagel chromatography (hexane/ethyl acetate=1:1,3:7) to provide 662 mg of(1α, 5α,7β)-3-(tert-butoxycarbonyl)-7-(methylsulfonyloxy)-3-azabicyclo[3.3.0]octane.Of the product, 205 mg was dissolved in 5 ml of dimethylformamide, andto the solution 205 mg of1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one and 185 mg ofpotassium carbonate were added, followed by heating to 80° C. andstirring for an overnight. Cooling the system off by standing, saturatedbrine was added to the reaction liquid and extracted with chloroform.The extract was washed with water and dried over anhydrous magnesiumsulfate. Distilling the solvent off, the residue was purified on silicagel chromatography (chloroform/ methanol=97:3, 10:1) to provide 32 mg of1-[1-[1-(1α, 5α,7α)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.Thirty (30) mg of the product was dissolved in 10 ml of 10% hydrogenchloride/methanol, stirred for an overnight, and the solvent wasdistilled off to provide 28 mg of the title compound.

[0675] Example 28

[0676] 1-[1-[(1α, 5α,7α)-3-(Pyrazinylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one

[0677] To 14 mg of 1-[1-[(1α, 5α,7α)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride, 0.1 ml of triethylamine, 1 ml of chloroform, 9 mg ofpyrazinecarboxylic acid, 14 mg of1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 10 mgof 1-hydroxybenzotriazole were added and stirred for an overnight atroom temperature. Saturated aqueous sodium hydrogencarbonate solutionwas added to the reaction liquid, which then was extracted withchloroform. The extract was dried on magnesium sulfate, concentrated andpurified on silica gel chromatography (chloroform/methanol=10:1) toprovide 4 mg of the title compound as a colorless, amorphous substance.

[0678]¹H-NMR(CDCl₃)δ: 1.51-1.70(2H,m),1.72-1.99(4H,m),2.04-2.23(2H,m),2.32-2.62(3H,m),2.80-3.00(2H,m),3.02-3.22(2H,m),3,50-3.72(2H,m),3.87-4.10(2H,m),4.23-4.50(1H,m),6.95-7.12(3H,m),7.19-7.40(1H,m),8.44(1H,s),8.55(1H,dd,J=1.5,2.6Hz),8.65(1H,d,J=2.6Hz),9.13(1H,d,J=1.5Hz) [M+H]⁺=433

[0679] Example 29

[0680] 1-[1-[(1α, 7α,9β)-4-(Pyrazinylcarbonyl)-4-azabicyclo[5.3.0]nonan-8-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one

[0681] Example 27 was repeated except that I-[l-[(1α,7α,9β)-4-azabicyclo[5.3.0]nonan-9-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-onewas used in place of 1-[1-[(1α, 5α,7β)-3-azabicyclo[3.3.0]octan-7-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,to provide the title compound as a colorless, amorphous substance.

[0682]¹H-NMR(CDCl₃)δ: 1.14-2.40(2H,m),1.55-2.61(15H,m),3.05-3.29(4H,m),3.62-3.82(1H,m),4.22-4.48(2H,m),6.96-7.15(3H,m),7.25-7.40(1H,m),8.55(1H,dd,J=1.6,2.6Hz),8.62(1H,d,J=2.6Hz),8.88(1H,d,J=1.6Hz),9.68(1H,s) [M+H]⁺=461

INDUSTRIAL UTILIZABILITY

[0683] Benzimidazolone derivatives of the present invention exhibitantagonism to muscarinic acetylcholine receptors, and are useful astreating agent and/or prophylactic of, for example, Parkinson's disease,drug-induced parkinsonism, dystonia, akinesia, pancreatitis,bilestone/cholecystitis, biliary dyskinesia, achalasia, pain, itch,cholinergic urticaria, irritable bowel syndrome, vomiting, nausea,dizziness, Meniere's disease, motion sickness such as space sickness,sea sickness and car sickness and urinary disturbance.

1. Benzimidazolone derivatives represented by a general formula [I]

[in which A ring

stands for a 5- to 8-membered aliphatic heterocyclic ring containing one nitrogen atom; R¹ binds to the benzene ring, standing for hydrogen, halogen, lower alkyl or lower alkoxy; R² stands for hydrogen or optionally phenyl-substituted lower alkyl; R^(3a) and R^(3b) stand for hydrogen or R³, R^(3a) standing for hydrogen when R^(3b) stands for R³ and R^(3a) standing for R³ when R^(3b) stands for hydrogen; R³ stands for hydrogen, halogen, hydroxyl, lower alkyl or lower alkenyl, or R³ and R⁴ together form a 3- to 6-membered carbocyclic ring with the carbon atoms to which they bind; R⁴ and R⁵ which are the same or different and bind to optional carbon atoms constituting said heterocyclic ring, stand for hydrogen, halogen, hydroxyl, lower alkyl or lower alkenyl, or R⁴ and R⁵ together form methylene group with the carbon atoms to which they bind, or R³ and R⁴ together form a 3- to 6-membered carbocyclic ring with the carbon atoms to which they bind, or R⁴ and R⁵ together form a 3- to 6-membered carbocyclic ring together with the carbon atoms to which they bind; R⁶ stands for aryl or heteroaryl which may have one, two or more substituents selected from the group consisting of halogen, cyano, nitro, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, halogenated lower alkyl, lower alkylamino, di-lower alkylamino, lower alkylthio, lower alkylsulfonyl, optionally fluorine-substituted lower alkoxy, lower acyl, lower acylamino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, di-lower alkylsulfamoyl, carbamoyloxy, lower alkylcarbamoyloxy, di-lower alkylcarbamoyloxy, lower alkoxycarbonylamino, sulfamoylamino, (lower alkylsulfamoyl)amino, (di- lower alkylsulfamoyl) amino, (lower alkylsulfamoyl)(lower alkyl)amino, (di-lower alkylsulfamoyl)(lower alkyl) amino, (lower alkylsulfonyl) amino, carbamoylamino, (lower alkylcarbamoyl)amino, (di-lower alkylcarbamoyl)amino and phenoxy; and Z stands for carbonyl (—CO—) or sulfonyl (—SO₂—)] or salts thereof.
 2. Benzimidazolone derivatives or salts thereof as described in claim 1, in which the benzimidazolone derivatives represented by the general formula [I] are those of a general formula [I-a]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶ and A ring

are same to those in claim 1].
 3. Benzimidazolone derivatives or salts thereof as described in claim 1, in which the benzimidazolone derivatives represented by the general formula [I] are those of a general formula [I-b]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶ and A ring

are same to those in claim 1].
 4. Benzimidazolone derivatives or salts thereof as described in claim 1, in which the 5- to 8-membered aliphatic heterocyclic ring represented by A ring

is one selected from the group consisting of pyrrolidine ring, piperidine ring, perhydroazepine ring, heptamethylenimine ring and 1,2,5,6-tetrahydropyridine ring.
 5. Benzimidazolone derivatives or salts thereof as described in claim 1, in which R⁶ is a group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2-tolyl, 3-tolyl, 4-tolyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-bromophenyl, 2-fluoro-4-chlorophenyl, 3-iodophenyl, 4-iodophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-(dimethylamino)phenyl, 3-(dimethylamino)phenyl, 2-cyanophenyl, 3-cyanophenyl, 2-(acetamido)phenyl, 3-(acetamido)phenyl, 3-(chloromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-(phenoxy)phenyl, 3-(phenoxy)phenyl, pyrazinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-chloro-3-pyridyl, 5-bromo-3-pyridyl, 5-cyano-3-pyridyl, 2-chloro-3-pyridyl, 6-chloro-3-pyridyl, 2,3-dichloropyridin-5-yl, 5-methyl-3-pyridyl, 2-methoxypyridyl, 2-phenoxypyridyl, 2- (methylthio)pyridyl, 2- methylpyridin-5-yl, 3-bromopyridin-5-yl, 2,6-dimethoxypyridyl, 2-(propylthio)pyridyl, 2-thienyl, 3-thienyl, 2-quinolyl and 3-quinolyl.
 6. Benzimidazolone derivatives or salts thereof as described in claim 1, in which the benzimidazolone derivative represented by the general formula [I] is [1[-[2-(1-benzoylpiperidin-4-yl)ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [1[-[2-[1-(4-chlorophenylsulfonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [1-[2-[1-[4-(trifluoromethoxy)phenylsulfonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(pyrazinylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [1-[2-[1,2,5,6-tetrahydro-1-(pyrazinylcarbonyl)-4-pyridyl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(pyrazinylcarbonyl)-3-methylene-piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, (S*) 1-[1-[2-[1-(pyrazinylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, (R*)-1-[1-[2-[1-(pyrazinylcarbonyI)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, (S*) 1-[1-[2-[1-(3-pyridylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, (R*)-1-[1-[2-[1-(3-pyridylcarbonyl)perhydroazepin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [1-[2-[1-(pyrazinylcarbonyl)piperidin-4-yl]propyllpiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [1[-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[[2-[1-(3-chlorobenzoyl)piperidin-4-yl]propyllpiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]-1-methylethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-hydroxy-2-[4-hydroxy-1-(3-pyridylcarbonyl)piperidin-4-yl]-ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(2-chlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(3-chlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(3-bromobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1l-[2-[1-(3-iodobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(3,5-dichlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3- dihydro-2H-benzimidazol-2-one, 1[1-[2-[1-(3,4-dichlorobenzoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-[(5-chloro-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3- dihydro-2H-benzimidazol-2-one, [1[-[2-[1-[(4,5-dichloro-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3- dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-[(5-bromo-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3- dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(2-thenoyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-(3-pyridylcarbonyl)piperidin-4-yl]ethyl]-piperidin-4-yl]-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-(1-pyrazinylcarbonylpiperidin-4-yl)ethyl]-piperidin-4-yl]-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-[(5,6-dichloro-3-pyridyl)carbonyl]-piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[1-[(2-propylthio-3-pyridyl)carbonyl]piperidin-4-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[4-fluoro-1-(pyrazinylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1[1-[2-[4-fluoro-1-(3-pyridylcarbonyl)piperidin-4-yl]propyl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[(1α, 5α, 7β)-3-(pyrazinylcarbonyl)-3-azabicyclo[3.3.0octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[l-[(1α, 5α, 7α)-3-(pyrazinylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [1[-[(1α, 5α, 76)-3-(3-pyridylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[(1α, 5α, 7β)-3-(3-pyridylcarbonyl)-3-azabicyclo[3.3.0]octan-7-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [1[1-[(1α, 7α,96)-4-(pyrazinylcarbonyl)-4-azabicyclo[5.3.0]nonan-9-yl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[-[2-[7-(3-pyridylcarbonyl)-7-azaspiro[3.5] nonan-2-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-[2-[7-(pyrazinylcarbonyl)-7-azaspiro[3.5]nonan-2-yl]ethyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, or 1-[1-[[6-(3-pyridylcarbonyl)-6-azaspiro[2.5]octan-1-yl]methyl]-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.
 7. A method for producing benzimidazolone derivatives represented by the general formula [I]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as described in claim 1] or salts thereof, which comprises a) a step of reacting a compound represented by a general formula [II]

[in which R¹ and R² are same as earlier defined] with a compound represented by a general formula [III]

[in which R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as earlier defined] to form a compound represented by a general formula [IV]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as earlier defined] and b) a step of reducing the compound of the general formula [IV] which is obtained in the step a).
 8. A method for producing benzimidazolone derivatives represented by the general formula [I]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as described in claim 1] or salts thereof, which comprises a step of reacting a compound represented by the general formula [II]

[in which R¹ and R² are same as earlier defined] with a compound represented by the general formula [III]

[in which R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as earlier defined] in the presence of a reagent which is selected from a group consisting of sodium borohydride, sodium cyanoborohydride, zinc cyanoborohydride and sodium triacetoxyborohydride.
 9. A method for producing benzimidazolone derivatives represented by the general formula [I]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as described in claim 1] or salts thereof, which comprises a step of reacting a compound represented by the general formula [II]

[in which R¹ and R² are same as earlier defined] with a compound represented by a general formula [V]

[in which R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as earlier defined; R⁷ stands for methylsulfonyl, phenylsulfonyl or p-tolylsulfonyl].
 10. A method for producing benzimidazolone derivatives represented by the general formula [I-a]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶ and A ring

are same as earlier defined] or salts thereof which comprises a step of reacting a compound of a general formula [VI]

[in which R¹, R² R^(3a), R^(3b), R⁴, R⁵ and A ring

are same as earlier defined] with a carboxylic acid represented by a general formula [VII-a] R⁶—COOH  [VII-a] [in which R⁶ is same as earlier defined] or an activated derivative thereof.
 11. A method for producing benzimidazolone derivatives represented by the general formula [I-b]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶ and A ring

are same as earlier defined] or salts thereof, which comprises a step of reacting a compound represented by the general formula [VI]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵ and A ring

are same as earlier defined] with a sulfonic acid of a general formula [VII-b]

[in which R⁶ is same as earlier defined] or an activated derivative thereof, in the presence or absence of a base.
 12. Pharmaceutical compositions containing benzimidazolone derivatives represented by the general formula [I]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as defined in claim 1] or salts thereof, and pharmaceutically acceptable adjuvants.
 13. Muscarinic receptor antagonists which contain benzimidazolone derivatives represented by the general formula [I]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as defined in claim 1] or salts thereof as the active ingredients.
 14. Drug for the treatment and/or prevention of Parkinson's disease, drug-induced parkinsonism, dystonia, akinesia, pancreatitis, bilestone/cholecystitis, biliary dyskinesia, achalasia, pain, itch, cholinergic urticaria, irritable bowel syndrome, vomiting, nausea, dizziness, Meniere's disease, motion sickness and urinary disturbance, which contain benzimidazolone derivatives represented by the general formula [I]

[in which R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, Z and A ring

are same as defined in claim 1] or salts thereof as the active ingredients. 